WO2022138888A1 - テトラヒドロキノリン誘導体及びその医薬用途 - Google Patents

テトラヒドロキノリン誘導体及びその医薬用途 Download PDF

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WO2022138888A1
WO2022138888A1 PCT/JP2021/048081 JP2021048081W WO2022138888A1 WO 2022138888 A1 WO2022138888 A1 WO 2022138888A1 JP 2021048081 W JP2021048081 W JP 2021048081W WO 2022138888 A1 WO2022138888 A1 WO 2022138888A1
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group
tetrahydroquinoline
phenyl
atom
hydrogen atom
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French (fr)
Japanese (ja)
Inventor
絢ヌネッツ 浅場
雄大 高橋
将史 山本
こずえ 高垣
摩利菜 野上
理一郎 辻
裕之 目黒
直哉 請川
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Toray Industries Inc
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Toray Industries Inc
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Priority to IL303307A priority Critical patent/IL303307A/en
Priority to AU2021410119A priority patent/AU2021410119A1/en
Priority to CN202180086287.2A priority patent/CN116648245A/zh
Priority to MX2023007476A priority patent/MX2023007476A/es
Priority to CA3201443A priority patent/CA3201443A1/en
Priority to EP21911025.1A priority patent/EP4269392A4/en
Priority to JP2021577857A priority patent/JPWO2022138888A1/ja
Priority to KR1020237012140A priority patent/KR102947968B1/ko
Priority to US18/268,667 priority patent/US12570639B2/en
Publication of WO2022138888A1 publication Critical patent/WO2022138888A1/ja
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    • C07D215/04—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to the ring carbon atoms
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    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
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    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
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    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D215/20—Oxygen atoms
    • C07D215/22—Oxygen atoms attached in position 2 or 4
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    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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Definitions

  • the present invention relates to a tetrahydroquinoline derivative and its pharmaceutical use.
  • Non-Patent Document 1 Ferroptosis is a decrease in antioxidant function such as a decrease in the amount of intracellular glutathione and glutathione perxidase 4 (GPX4) due to various stimuli, and the progress of a divalent iron-dependent reaction causes the death of intracellular lipid peroxide. It is a reaction that rises to a certain level and causes cell death.
  • GPX4 glutathione perxidase 4
  • multiple sclerosis in which a decrease in GPX4 has been reported in the patient's brain and has been suggested to be associated with ferrotosis, is demyelination in which the myelin sheath covering nerve fibers such as the brain, spinal cord and optic nerve is destroyed. It is a disease in which the disorder progresses while repeating recurrence and remission. Symptoms vary depending on the lesion site, and are known to exhibit various neurological symptoms such as visual impairment, paralysis of limbs, sensory impairment, and gait disturbance (Non-Patent Documents 7 and 8).
  • Non-Patent Documents 1 and 9 Aniline derivatives such as Ferroptin-1 are known as compounds exhibiting a ferrotosis inhibitory action. Further, it is disclosed that a tetrahydroquinoxaline derivative and a 3,4-dihydro-2H-benzo- [1,4] oxazine derivative also have a ferrotosis inhibitory action (Patent Documents 1 and 2).
  • Non-Patent Document 10 It has been reported that a radical scavenging action is important for the manifestation of a ferrotosis inhibitory action. Further, it is disclosed that the tetrahydroquinoxaline derivative described in Patent Document 1 has a strong radical scavenging action and, as a result, exhibits a ferrotosis inhibitory action (Non-Patent Documents 11 and 12).
  • Patent Documents 3 to 7 disclose tetrahydroquinoline derivatives having an antiviral effect, an antitumor effect, a pain therapeutic effect, or an immune response modifying effect.
  • Patent Documents 1 to 7 and Non-Patent Documents 1 to 12 do not disclose the ferrotosis-inhibiting action of the tetrahydroquinoline derivative, and do not suggest the possibility thereof.
  • an object of the present invention is to provide a compound which has a ferrotosis inhibitory action and exerts a therapeutic or preventive effect on a disease, disorder or syndrome related to ferrotosis inhibition such as multiple sclerosis.
  • the present invention includes the following.
  • [1] A tetrahydroquinoline derivative represented by the following general formula (I) or a pharmacologically acceptable salt thereof.
  • R 1x is a hydrogen atom, a phenyl group (the phenyl group may be substituted with the following substituent or the following fused ring group may be formed), or a frill group, a thienyl group, A 5- or 6-membered ring heteroaryl group selected from the group consisting of a pyrrolyl group, an imidazolyl group, a pyrazolyl group, a thiazolyl group, an isothiazolyl group, an oxazolyl group, an isooxazolyl group and a pyridyl group (the heteroaryl group is substituted with the following substituents).
  • R 1y represents a hydrogen atom, 4-hydroxymethylphenyl group, 4-aminocarbonylphenyl group, 4-acetamidephenyl group, 4-aminosulfonylphenyl group or 4-methylsulfonylphenyl (where R 1x is a hydrogen atom).
  • R 1y is a substituent other than a hydrogen atom, and when R 1x is a substituent other than a hydrogen atom, R 1y is a hydrogen atom).
  • R 2 , R 4 and R 5 are all hydrogen atoms, or R 2 and R 4 have one of a fluorine atom, a chlorine atom, a methoxy group or one hydrogen atom. Is a methyl group that may be substituted with a hydroxy group, and the other and R 5 are hydrogen atoms, or R 2 and R 4 are both hydrogen atoms and R 5 is a fluorine atom or chlorine atom.
  • R 3 is a hydrogen atom, a halogen atom, an alkyl group having 1 to 3 carbon atoms in which 1 to 3 arbitrary hydrogen atoms may be independently substituted with a hydroxy group or a fluorine atom, and 3-hydroxyoxetane.
  • 3-Il group, hydroxy group, 1 to 3 arbitrary hydrogen atoms may be substituted with fluorine atoms, alkoxy groups with 1 to 3 carbon atoms, methoxycarbonyl groups, -NR 9 R 10 , -CH 2 NR.
  • Rv represents a hydrogen atom
  • R w represents a hydrogen atom
  • R 1x is a phenyl group (in the case of any one hydrogen atom of the phenyl group, a halogen atom, 1 to 3 arbitrary hydrogen atoms may be substituted with a fluorine atom, and the number of carbon atoms is 1 to 3).
  • 1 to 3 selected from the group consisting of an alkoxy group having 1 to 3 carbon atoms, a cyano group, a methoxycarbonyl group and -NHCOR 8 in which 1 to 3 arbitrary hydrogen atoms may be substituted with a fluorine atom.
  • R 3 is an alkyl group having 1 to 3 carbon atoms in which 1 to 3 arbitrary hydrogen atoms are substituted with fluorine atoms, and 1 to 3 carbon atoms in which 1 arbitrary hydrogen atom is substituted with a hydroxy group.
  • R 8 represents a hydrogen atom or an alkyl group having 1 to 3 carbon atoms.
  • R 9 represents a hydrogen atom
  • R 10 represents a hydrogen atom, -COR 15 or an alkylsulfonyl group having 1 to 3 carbon atoms, or R 9 and R 10 are united to represent-(CH 2 ) n- , and n represents 4 or 5 and represents R 11 and R 12 collectively represent ⁇ (CH 2 ) m ⁇ .
  • m represents 4 or 5, where any one methylene group may be substituted with an oxygen atom.
  • R 13 represents a hydrogen atom or a methyl group.
  • R 14 has a hydrogen atom, a methyl group, an ethyl group, an isopropyl group, a tert-butyl group, a 2-hydroxyethyl group, and one arbitrary carbon atom having 3 or 4 carbon atoms may be substituted with an oxygen atom.
  • R 15 represents an alkyl group having 1 to 5 carbon atoms, an alkoxy group having 1 to 5 carbon atoms, or ⁇ NHR 16 .
  • R 16 represents a hydrogen atom or an alkyl group having 1 to 5 carbon atoms.
  • R 1x is a hydrogen atom, a phenyl group (one arbitrary hydrogen atom of the phenyl group is an alkyl group having 1 to 3 carbon atoms in which one arbitrary hydrogen atom is substituted with a hydroxy group,-.
  • CONR 6 R 7 aminosulfonyl group, methylsulfonylamino group, aminosulfonylamino group or alkylsulfonyl group having 1 to 3 carbon atoms is substituted, or one hydrogen atom at the meta position of the phenyl group is a cyano group.
  • R 1x is a fused ring group in which a phenyl group is fused with one ring selected from the group consisting of pyrrolidine-2-one, piperidine-2-one and 1,3-dioxolane (one of the fused ring groups).
  • R 3 has 1 to 3 carbon atoms in which a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, 1 to 3 arbitrary hydrogen atoms may be substituted with a fluorine atom, or 1 arbitrary hydrogen atom may be substituted with a hydroxy group.
  • R 6 and R 7 may form a piperidine ring, a morpholine ring, a piperazine ring or an N-methylpiperazine ring together with the nitrogen atom bonded to them.
  • R 9 represents a hydrogen atom
  • R 10 represents a hydrogen atom, -COR 15 or an alkylsulfonyl group having 1 to 3 carbon atoms, or R 9 and R 10 are united to represent-(CH 2 ) n- , and n represents 4 or 5 and represents R 11 and R 12 collectively represent ⁇ (CH 2 ) m ⁇ . m represents 4 or 5, where any one methylene group may be substituted with an oxygen atom.
  • R 13 represents a hydrogen atom or a methyl group.
  • R 14 has a hydrogen atom, a methyl group, an ethyl group, an isopropyl group, a tert-butyl group, a 2-hydroxyethyl group, and one arbitrary carbon atom having 3 or 4 carbon atoms may be substituted with an oxygen atom.
  • R 15 represents an alkyl group having 1 to 5 carbon atoms, an alkoxy group having 1 to 5 carbon atoms, or ⁇ NHR 16 .
  • R 16 represents a hydrogen atom or an alkyl group having 1 to 5 carbon atoms (provided that methyl 2- (4-methoxyphenyl) -1,2,3,4-tetrahydroquinoline-6-carboxylate and 2- (benzo).
  • [D] [1,3] dioxol-5-yl) -1,2,3,4-tetrahydroquinoline is excluded).
  • R 1x is a phenyl group (the phenyl group may be substituted with the following substituent or may form the following fused ring group), or a frill group, a thienyl group, a pyrrolyl group, or an imidazolyl.
  • a 5- or 6-membered ring heteroaryl group selected from the group consisting of a group, a pyrazolyl group, a thiazolyl group, an isothiazolyl group, an oxazolyl group, an isooxazolyl group and a pyridyl group (the heteroaryl group may be substituted with the following substituents).
  • R 2 , R 4 and R 5 are all hydrogen atoms, or R 2 and R 4 have one of a fluorine atom, a chlorine atom, a methoxy group or one hydrogen atom. Is a methyl group that may be substituted with a hydroxy group, and the other and R 5 are hydrogen atoms, or R 2 and R 4 are both hydrogen atoms and R 5 is a fluorine atom or chlorine atom.
  • Rv is a hydrogen atom
  • R w is a hydrogen atom
  • R 1x is a phenyl group (in the case of any one hydrogen atom of the phenyl group, a halogen atom, 1 to 3 arbitrary hydrogen atoms may be substituted with a fluorine atom, and the number of carbon atoms is 1 to 3).
  • 1 to 3 selected from the group consisting of an alkoxy group having 1 to 3 carbon atoms, a cyano group, a methoxycarbonyl group and -NHCOR 8 in which 1 to 3 arbitrary hydrogen atoms may be substituted with a fluorine atom.
  • R 3 is an alkyl group having 1 to 3 carbon atoms in which 1 to 3 arbitrary hydrogen atoms are substituted with fluorine atoms, and 1 to 3 carbon atoms in which 1 arbitrary hydrogen atom is substituted with a hydroxy group.
  • R 8 is a hydrogen atom or an alkyl group having 1 to 3 carbon atoms.
  • R 9 is a hydrogen atom
  • R 10 is a hydrogen atom, -COR 15 or an alkylsulfonyl group having 1 to 3 carbon atoms, or is R 9 and R 10 are united- (CH 2 ) n- , and n is 4 or 5
  • R 11 and R 12 are integrally- (CH 2 ) m- , and are m is 4 or 5, where any one methylene group may be substituted with an oxygen atom.
  • R 13 is a hydrogen atom and R 14 is a hydrogen atom, a methyl group, an ethyl group, an isopropyl group or a tert-butyl group, or is R 13 and R 14 may form an azetidine ring in which one arbitrary hydrogen atom may be substituted with a hydroxy group together with the nitrogen atom bonded to them.
  • R 15 is an alkyl group having 1 to 5 carbon atoms, an alkoxy group having 1 to 5 carbon atoms, or ⁇ NHR 16 .
  • R 16 is a hydrogen atom or an alkyl group having 1 to 5 carbon atoms.
  • R 1x is a phenyl group (one arbitrary hydrogen atom of the phenyl group is an alkyl group having 1 to 3 carbon atoms in which one arbitrary hydrogen atom is substituted with a hydroxy group, -CONR 6 R. 7. Is it substituted with an aminosulfonyl group or an alkylsulfonyl group having 1 to 3 carbon atoms, or one hydrogen atom at the meta position of the phenyl group is substituted with a cyano group, or at the para position of the phenyl group.
  • R 1x is a fused ring group in which a phenyl group is fused with one ring selected from the group consisting of pyrrolidine-2-one, piperidine-2-one and 1,3-dioxolane (one of the fused ring groups).
  • R 3 has 1 to 3 carbon atoms in which a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, 1 to 3 arbitrary hydrogen atoms may be substituted with a fluorine atom, or 1 arbitrary hydrogen atom may be substituted with a hydroxy group.
  • R 6 and R 7 are each independently a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, or R 6 and R 7 may form a piperidine ring, a morpholine ring, a piperazine ring or an N-methylpiperazine ring together with the nitrogen atom bonded to them.
  • R 9 is a hydrogen atom
  • R 10 is a hydrogen atom, -COR 15 or an alkylsulfonyl group having 1 to 3 carbon atoms, or is R 9 and R 10 are united- (CH 2 ) n- , and n is 4 or 5
  • R 11 and R 12 are integrally- (CH 2 ) m- , and are m is 4 or 5, where any one methylene group may be substituted with an oxygen atom.
  • R 13 is a hydrogen atom and R 14 is a hydrogen atom, a methyl group, an ethyl group, an isopropyl group or a tert-butyl group, or is R 13 and R 14 may form an azetidine ring in which one arbitrary hydrogen atom may be substituted with a hydroxy group together with the nitrogen atom bonded to them.
  • R 15 is an alkyl group having 1 to 5 carbon atoms, an alkoxy group having 1 to 5 carbon atoms, or ⁇ NHR 16 .
  • R 16 is a hydrogen atom or an alkyl group having 1 to 5 carbon atoms (however, 2- (4-methoxyphenyl) -1,2,3,4-tetrahydroquinoline-6-carboxylate methyl and 2- (benzo).
  • R1x is a phenyl group (the phenyl group may be substituted with the following substituents).
  • R1y is a hydrogen atom and In the combination of R2 , R4 and R5, either R2 , R4 and R5 are all hydrogen atoms, or R2 and R4 have one fluorine atom, chlorine atom or methyl group and the other and the other.
  • R 5 is a hydrogen atom
  • R v is a hydrogen atom
  • R w is a hydrogen atom.
  • R 1x is substituted with a phenyl group (the hydrogen atom at the para position of the phenyl group is substituted with one substituent selected from the group consisting of a fluorine atom, a trifluoromethyl group, a cyano group and an acetamide group.
  • R 3 is a trifluoromethoxy group, a hydroxymethyl group or -CH 2 CONR 13 R 14 (where R 2 is a methyl group and R 4 and R 5 are both hydrogen atoms, then R 3 is hydrogen. It may be an atom)
  • R 13 is a hydrogen atom or a methyl group.
  • R 14 is a tert-butyl group, a 2-hydroxyethyl group, a cyclopropyl group, a cyclobutyl group or an oxetane-3-yl group, or is Piperazine ring, piperazine-2-one ring, azetidine ring, 3,3-difluoroazetidine ring, 3,3-dimethylazetidine ring, 3-hydroxy, along with the nitrogen atom to which R 13 and R 14 are attached. It may form an azetidine ring or a 3-methoxy azetidine ring.
  • R 1x is a phenyl group (the hydrogen atom at the para position of the phenyl group is substituted with a trifluoromethoxy group, an aminocarbonyl group, an aminosulfonyl group, a methylsulfonylamino group or a methylsulfonyl group).
  • R 3 is a hydrogen atom, a fluorine atom, a chlorine atom, a methyl group, a hydroxymethyl group, a trifluoromethoxy group or -CH 2 CONR 13 R 14 .
  • R 13 is a hydrogen atom or a methyl group.
  • R 14 is a tert-butyl group, a 2-hydroxyethyl group, a cyclopropyl group, a cyclobutyl group or an oxetane-3-yl group, or is Piperazine ring, piperazine-2-one ring, azetidine ring, 3,3-difluoroazetidine ring, 3,3-dimethylazetidine ring, 3-hydroxy, along with the nitrogen atom to which R 13 and R 14 are attached.
  • the tetrahydroquinoline derivative according to [1] or [2] or a pharmacologically acceptable salt thereof which may form an azetidine ring or a 3-methoxy azetidine ring.
  • R 1x is a 5- or 6-membered ring heteroaryl group containing 1 or 2 heteroatoms selected from a hydrogen atom, an aryl group or a nitrogen atom, an oxygen atom and a sulfur atom (the aryl group and the 5 or 6).
  • One or two arbitrary hydrogen atoms of the member ring heteroaryl group are independently substituted with a halogen atom and one to three arbitrary hydrogen atoms are independently substituted with a hydroxy group or a fluorine atom, respectively.
  • a good alkyl group having 1 to 3 carbon atoms, 1 to 3 arbitrary hydrogen atoms may be substituted with a fluorine atom, an alkoxy group having 1 to 3 carbon atoms, a cyano group, a methoxycarbonyl group, -CONR 6 R 7 , -NHCOR 8 , aminosulfonyl group, alkylsulfonylamino group with 1-3 carbon atoms, aminosulfonylamino group or alkylsulfonyl group with 1-3 carbon atoms).
  • R 1x when the aryl group is a phenyl group (the phenyl group may form the following fused ring group), the phenyl group is used as a constituent atom of the 5- and 6-membered lactam rings and the ring.
  • R 1y represents a hydrogen atom, a phenyl group, a 4-hydroxymethylphenyl group, a 4-aminocarbonylphenyl group, a 4-acetamidophenyl group, a 4-aminosulfonylphenyl group, a 4-methylsulfonylphenyl group or a 3-pyridyl group. (Except that both R 1x and R 1y are hydrogen atoms), In the combination of R2 , R4 and R5, is R2 , R4 and R5 all hydrogen atoms?
  • R2 , R4 and R5 is a methyl group in which a halogen atom, a methoxy group or one hydrogen atom may be substituted with a hydroxy group, and the other two are hydrogen atoms.
  • R 3 is a hydrogen atom, a halogen atom, an alkyl group having 1 to 3 carbon atoms in which 1 to 3 arbitrary hydrogen atoms may be independently substituted with a hydroxy group or a fluorine atom, and 3-hydroxyoxetane.
  • 3-yl group, hydroxy group, 1 to 3 arbitrary hydrogen atoms may be substituted with fluorine atoms, alkoxy groups with 1 to 3 carbon atoms, methoxycarbonyl groups, -NR 9 R 10 , -CH 2 NR.
  • R 6 and R 7 each independently represent a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, or each of them represents a hydrogen atom or an alkyl group having 1 to 3 carbon atoms.
  • R 6 and R 7 collectively represent ⁇ (CH 2 ) h ⁇ .
  • h represents an integer of 3 to 5, where any one methylene group may be substituted with an oxygen atom, —NH— or —N (CH 3 ) —.
  • R 8 represents a hydrogen atom or an alkyl group having 1 to 3 carbon atoms.
  • R 9 and R 10 each independently represent a hydrogen atom, -COR 15 or an alkylsulfonyl group having 1 to 3 carbon atoms, or R 9 and R 10 collectively represent ⁇ (CH 2 ) n ⁇ .
  • n represents an integer of 3 to 6 and represents R 11 and R 12 collectively represent ⁇ (CH 2 ) m ⁇ .
  • m represents an integer of 3 to 5, where any one methylene group may be substituted with an oxygen atom.
  • Each of R 13 and R 14 has a hydrogen atom, an alkyl group having 1 to 5 carbon atoms, a 2-hydroxyethyl group, and an arbitrary carbon atom having 1 carbon atom substituted with an oxygen atom. Alternatively, it represents a cycloalkyl group of 4, or a methyl group in which any one carbon atom is substituted with a cycloalkyl group having 3 or 4 carbon atoms, which may be substituted with a nitrogen atom or an oxygen atom.
  • one or two arbitrary hydrogen atoms are a fluorine atom, a methyl group, a hydroxy group or a methoxy group, or one arbitrary CH two group is an oxygen atom and a nitrogen atom.
  • R 16 represents a hydrogen atom or an alkyl group having 1 to 5 carbon atoms.
  • R v represents a hydrogen atom, a methyl group in which one arbitrary hydrogen atom may be substituted with a hydroxy group or a methoxycarbonyl group, or a methoxycarbonyl group.
  • R w represents a hydrogen atom, a methyl group, a hydroxymethyl group or a methoxycarbonyl group (where 2-phenyl-1,2,3,4-tetrahydroquinoline and 3-phenyl-1,2,3,4-tetrahydro). (Excluding quinoline). ]
  • R 1x is a phenyl group (one arbitrary hydrogen atom of the phenyl group is a halogen atom, 1 to 3 arbitrary hydrogen atoms are fluorine atoms, or one arbitrary hydrogen atom is a hydroxy group.
  • a 5- or 6-membered ring heteroaryl group selected from the group consisting of a group, an isothiazolyl group, an oxazolyl group, an isooxazolyl group and a pyridyl group (one arbitrary hydrogen atom of the 5 or 6-membered ring heteroaryl group has a carbon number of carbon atoms.
  • R1x is a fused ring group (one of the fused ring groups) in which a phenyl group and one ring selected from the group consisting of pyrrolidine-2-one, piperidine-2-one and 1,3-dioxolane are condensed. Any hydrogen atom in the above may be substituted with a methyl group).
  • R1y is a hydrogen atom and In the combination of R 2 , R 4 and R 5 , R 2 , R 4 and R 5 are all hydrogen atoms, or R 2 and R 4 have one of a fluorine atom, a chlorine atom, a methoxy group or one hydrogen atom. Is a methyl group that may be substituted with a hydroxy group, and the other and R 5 are hydrogen atoms, or R 2 and R 4 are both hydrogen atoms and R 5 is a fluorine atom or chlorine atom.
  • R 3 has 1 to 3 carbon atoms in which a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, 1 to 3 arbitrary hydrogen atoms may be substituted with a fluorine atom, or 1 arbitrary hydrogen atom may be substituted with a hydroxy group.
  • R 6 and R 7 are each independently a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, or R 6 and R 7 may form a piperidine ring, a morpholine ring, a piperazine ring or an N-methylpiperazine ring together with a nitrogen atom bonded to them.
  • R 8 is a hydrogen atom or an alkyl group having 1 to 3 carbon atoms.
  • R 9 is a hydrogen atom
  • R 10 is a hydrogen atom, -COR 15 or an alkylsulfonyl group having 1 to 3 carbon atoms, or is R 9 and R 10 are integrally- (CH 2 ) n- , and are n is 4 or 5
  • R 11 and R 12 are integrally- (CH 2 ) m- , and are m is 4 or 5, where any one methylene group may be substituted with an oxygen atom.
  • R 13 is a hydrogen atom and R 14 is a hydrogen atom, a methyl group, an ethyl group, an isopropyl group or a tert-butyl group, or is R 13 and R 14 may form an azetidine ring in which one arbitrary hydrogen atom may be substituted with a hydroxy group together with the nitrogen atom bonded to them.
  • R 15 is an alkyl group having 1 to 5 carbon atoms, an alkoxy group having 1 to 5 carbon atoms, or ⁇ NHR 16 .
  • R 16 is a hydrogen atom or an alkyl group having 1 to 5 carbon atoms.
  • Rv is a hydrogen atom
  • R w is a hydrogen atom (excluding 2-phenyl-1,2,3,4-tetrahydroquinoline)
  • the active ingredient is the tetrahydroquinoline derivative according to [7] or a pharmacologically acceptable salt thereof. Contains as a drug.
  • R1x is a phenyl group (the phenyl group may have the following substituent or may form the following fused ring group), or a frill group, a thienyl group, a pyrrolyl group, or an imidazolyl.
  • R1y is a hydrogen atom and In the combination of R 2 , R 4 and R 5 , R 2 , R 4 and R 5 are all hydrogen atoms, or R 2 and R 4 have one of a fluorine atom, a chlorine atom, a methoxy group or one hydrogen atom. Is a methyl group that may be substituted with a hydroxy group, and the other and R 5 are hydrogen atoms, or R 2 and R 4 are both hydrogen atoms and R 5 is a fluorine atom or chlorine atom.
  • Rv is a hydrogen atom
  • R w is a hydrogen atom
  • R 1x is a phenyl group (in the case of any one hydrogen atom of the phenyl group, a halogen atom, 1 to 3 arbitrary hydrogen atoms may be substituted with a fluorine atom, and the number of carbon atoms is 1 to 3).
  • 1 to 3 selected from the group consisting of an alkoxy group having 1 to 3 carbon atoms, a cyano group, a methoxycarbonyl group and -NHCOR 8 in which 1 to 3 arbitrary hydrogen atoms may be substituted with a fluorine atom.
  • R 3 is an alkyl group having 1 to 3 carbon atoms in which 1 to 3 arbitrary hydrogen atoms are substituted with fluorine atoms, and 1 to 3 carbon atoms in which 1 arbitrary hydrogen atom is substituted with a hydroxy group.
  • R 8 is a hydrogen atom or an alkyl group having 1 to 3 carbon atoms.
  • R 9 is a hydrogen atom
  • R 10 is a hydrogen atom, -COR 15 or an alkylsulfonyl group having 1 to 3 carbon atoms, or is R 9 and R 10 are united- (CH 2 ) n- , and n is 4 or 5
  • R 11 and R 12 are integrally- (CH 2 ) m- , and are m is 4 or 5, where any one methylene group may be substituted with an oxygen atom.
  • R 13 is a hydrogen atom and R 14 is a hydrogen atom, a methyl group, an ethyl group, an isopropyl group or a tert-butyl group, or is R 13 and R 14 may form an azetidine ring in which one arbitrary hydrogen atom may be substituted with a hydroxy group together with the nitrogen atom bonded to them.
  • R 15 is an alkyl group having 1 to 5 carbon atoms, an alkoxy group having 1 to 5 carbon atoms, or ⁇ NHR 16 .
  • R 16 is a hydrogen atom or an alkyl group having 1 to 5 carbon atoms.
  • R 1x is a phenyl group (one arbitrary hydrogen atom of the phenyl group is an alkyl group having 1 to 3 carbon atoms in which one arbitrary hydrogen atom is substituted with a hydroxy group, -CONR 6 R. 7. Is it substituted with an aminosulfonyl group or an alkylsulfonyl group having 1 to 3 carbon atoms, or one hydrogen atom at the meta position of the phenyl group is substituted with a cyano group, or at the para position of the phenyl group.
  • R 1x is a fused ring group in which a phenyl group is fused with one ring selected from the group consisting of pyrrolidine-2-one, piperidine-2-one and 1,3-dioxolane (one of the fused ring groups).
  • R 3 has 1 to 3 carbon atoms in which a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, 1 to 3 arbitrary hydrogen atoms may be substituted with a fluorine atom, or 1 arbitrary hydrogen atom may be substituted with a hydroxy group.
  • R 6 and R 7 are each independently a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, or R 6 and R 7 may form a piperidine ring, a morpholine ring, a piperazine ring or an N-methylpiperazine ring together with the nitrogen atom bonded to them.
  • R 9 is a hydrogen atom
  • R 10 is a hydrogen atom, -COR 15 or an alkylsulfonyl group having 1 to 3 carbon atoms, or is R 9 and R 10 are united- (CH 2 ) n- , and n is 4 or 5
  • R 11 and R 12 are integrally- (CH 2 ) m- , and are m is 4 or 5, where any one methylene group may be substituted with an oxygen atom.
  • R 13 is a hydrogen atom and R 14 is a hydrogen atom, a methyl group, an ethyl group, an isopropyl group or a tert-butyl group, or is R 13 and R 14 may form an azetidine ring in which one arbitrary hydrogen atom may be substituted with a hydroxy group together with the nitrogen atom bonded to them.
  • R 15 is an alkyl group having 1 to 5 carbon atoms, an alkoxy group having 1 to 5 carbon atoms, or ⁇ NHR 16 .
  • R 16 is a pharmaceutical agent containing, as an active ingredient, the tetrahydroquinoline derivative according to [7] or [8], which is a hydrogen atom or an alkyl group having 1 to 5 carbon atoms, or a pharmacologically acceptable salt thereof.
  • R1x is a phenyl group (the hydrogen atom at the para position of the phenyl group is a fluorine atom, a trifluoromethyl group, a trifluoromethoxy group, a cyano group, an aminocarbonyl group, an acetamide group, an aminosulfonyl group, or a methylsulfonyl group. It may be substituted with an amino group or a methylsulfonyl group).
  • R1y is a hydrogen atom and In the combination of R2 , R4 and R5, either R2 , R4 and R5 are all hydrogen atoms, or R2 and R4 have one fluorine atom, chlorine atom or methyl group and the other and the other.
  • R 5 is a hydrogen atom
  • R 3 is a hydrogen atom, a fluorine atom, a chlorine atom, a methyl group, a hydroxymethyl group, a trifluoromethoxy group or -CH 2 CONR 13 R 14 .
  • R 13 is a hydrogen atom or a methyl group.
  • R 14 is a tert-butyl group, a 2-hydroxyethyl group, a cyclopropyl group, a cyclobutyl group or an oxetane-3-yl group, or is Piperazine ring, piperazine-2-one ring, azetidine ring, 3,3-difluoroazetidine ring, 3,3-dimethylazetidine ring, 3-hydroxy, along with the nitrogen atom to which R 13 and R 14 are attached. It may form an azetidine ring or a 3-methoxy azetidine ring.
  • Rv is a hydrogen atom
  • R w is a hydrogen atom (excluding 2-phenyl-1,2,3,4-tetrahydroquinoline), the tetrahydroquinoline derivative according to any one of [7] to [9], or its pharmacological A pharmaceutical product containing an acceptable salt as an active ingredient.
  • the present invention includes a ferroptosis inhibitor containing a tetrahydroquinoline derivative represented by the following general formula (I) or a pharmacologically acceptable salt thereof as an active ingredient. ..
  • R 1x is a 5- or 6-membered ring heteroaryl group containing 1 or 2 heteroatoms selected from a hydrogen atom, an aryl group or a nitrogen atom, an oxygen atom and a sulfur atom (the aryl group and the 5 or 6).
  • One or two arbitrary hydrogen atoms of the member ring heteroaryl group are independently substituted with a halogen atom and one to three arbitrary hydrogen atoms are independently substituted with a hydroxy group or a fluorine atom, respectively.
  • a good alkyl group having 1 to 3 carbon atoms, 1 to 3 arbitrary hydrogen atoms may be substituted with a fluorine atom, an alkoxy group having 1 to 3 carbon atoms, a cyano group, a methoxycarbonyl group, -CONR 6 R 7 , -NHCOR 8 , aminosulfonyl group, alkylsulfonylamino group having 1-3 carbon atoms, aminosulfonylamino group or alkylsulfonyl group having 1-3 carbon atoms).
  • R 1x when the aryl group is a phenyl group (the phenyl group may form the following fused ring group), the phenyl group is used as a constituent atom of the 5- and 6-membered lactam rings and the ring.
  • R 1y represents a hydrogen atom, a phenyl group, a 4-hydroxymethylphenyl group, a 4-aminocarbonylphenyl group, a 4-acetamidophenyl group, a 4-aminosulfonylphenyl group, a 4-methylsulfonylphenyl group or a 3-pyridyl group. (Except that both R 1x and R 1y are hydrogen atoms), In the combination of R2 , R4 and R5, is R2 , R4 and R5 all hydrogen atoms?
  • R2 , R4 and R5 is a methyl group in which a halogen atom, a methoxy group or one hydrogen atom may be substituted with a hydroxy group, and the other two are hydrogen atoms.
  • R 3 is a hydrogen atom, a halogen atom, an alkyl group having 1 to 3 carbon atoms in which 1 to 3 arbitrary hydrogen atoms may be independently substituted with a hydroxy group or a fluorine atom, and 3-hydroxyoxetane.
  • 3-Il group, hydroxy group, 1 to 3 arbitrary hydrogen atoms may be substituted with fluorine atoms, alkoxy groups with 1 to 3 carbon atoms, methoxycarbonyl groups, -NR 9 R 10 , -CH 2 NR.
  • R 6 and R 7 each independently represent a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, or each of them represents a hydrogen atom or an alkyl group having 1 to 3 carbon atoms.
  • R 6 and R 7 collectively represent ⁇ (CH 2 ) h ⁇ .
  • h represents an integer of 3 to 5, where any one methylene group may be substituted with an oxygen atom, —NH— or —N (CH 3 ) —.
  • R 8 represents a hydrogen atom or an alkyl group having 1 to 3 carbon atoms.
  • R 9 and R 10 each independently represent a hydrogen atom, -COR 15 or an alkylsulfonyl group having 1 to 3 carbon atoms, or R 9 and R 10 collectively represent ⁇ (CH 2 ) n ⁇ .
  • n represents an integer of 3 to 6 and represents R 11 and R 12 collectively represent ⁇ (CH 2 ) m ⁇ .
  • m represents an integer of 3 to 5, where any one methylene group may be substituted with an oxygen atom.
  • Each of R 13 and R 14 has a hydrogen atom, an alkyl group having 1 to 5 carbon atoms, a 2-hydroxyethyl group, and an arbitrary carbon atom having 1 carbon atom substituted with an oxygen atom. Alternatively, it represents a cycloalkyl group of 4, or a methyl group in which any one carbon atom is substituted with a cycloalkyl group having 3 or 4 carbon atoms, which may be substituted with a nitrogen atom or an oxygen atom.
  • one or two arbitrary hydrogen atoms are a fluorine atom, a methyl group, a hydroxy group or a methoxy group, or one arbitrary CH two group is an oxygen atom and a nitrogen atom.
  • R 16 represents a hydrogen atom or an alkyl group having 1 to 5 carbon atoms.
  • R v represents a hydrogen atom, a methyl group in which one arbitrary hydrogen atom may be substituted with a hydroxy group or a methoxycarbonyl group, or a methoxycarbonyl group.
  • R w represents a hydrogen atom, a methyl group, a hydroxymethyl group or a methoxycarbonyl group.
  • the present invention includes the use of the above-mentioned tetrahydroquinoline derivative (I) or a pharmacologically acceptable salt thereof in the production of a ferrotosis inhibitor.
  • the present invention relates to the use of the tetrahydroquinoline derivative (I) or a pharmacologically acceptable salt thereof in the manufacture of a pharmaceutical product, preferably a disease, disorder or a disorder associated with inhibition of ferrotosis.
  • a pharmaceutical product preferably a disease, disorder or a disorder associated with inhibition of ferrotosis.
  • the invention is the above tetrahydroquinoline derivative (I) or a pharmacologically acceptable salt thereof for use in the treatment or prevention of diseases, disorders or syndromes associated with ferrotosis inhibition.
  • the present invention is a method for treating or preventing a disease, disorder or syndrome associated with inhibition of ferrotosis, wherein an effective amount of the above tetrahydroquinoline derivative (I) or a pharmacologically acceptable thereof is acceptable.
  • a method comprising administering the salt to be administered to a subject in need thereof, preferably a method for treating or preventing multiple sclerosis, wherein an effective amount of the above-mentioned tetrahydroquinoline derivative (I) or a drug thereof.
  • the drug of the present invention can be used for multiple sclerosis and the like. It is effective in treating or preventing diseases, disorders or syndromes associated with inhibition of ferrotosis.
  • the tetrahydroquinoline derivative which is the active ingredient of the pharmaceutical product of the present invention or a pharmacologically acceptable salt thereof is characterized by being represented by the following general formula (I).
  • R 1x is a 5- or 6-membered ring heteroaryl group containing 1 or 2 heteroatoms selected from a hydrogen atom, an aryl group or a nitrogen atom, an oxygen atom and a sulfur atom (the aryl group and the 5 or 6).
  • One or two arbitrary hydrogen atoms of the member ring heteroaryl group are independently substituted with a halogen atom and one to three arbitrary hydrogen atoms are independently substituted with a hydroxy group or a fluorine atom, respectively.
  • a good alkyl group having 1 to 3 carbon atoms, 1 to 3 arbitrary hydrogen atoms may be substituted with a fluorine atom, an alkoxy group having 1 to 3 carbon atoms, a cyano group, a methoxycarbonyl group, -CONR 6 R 7 , -NHCOR 8 , aminosulfonyl group, alkylsulfonylamino group with 1-3 carbon atoms, aminosulfonylamino group or alkylsulfonyl group with 1-3 carbon atoms).
  • R 1x when the aryl group is a phenyl group (the phenyl group may form the following fused ring group), the phenyl group is used as a constituent atom of the 5- and 6-membered lactam rings and the ring.
  • R 1y represents a hydrogen atom, a phenyl group, a 4-hydroxymethylphenyl group, a 4-aminocarbonylphenyl group, a 4-acetamidophenyl group, a 4-aminosulfonylphenyl group, a 4-methylsulfonylphenyl group or a 3-pyridyl group. (Except that both R 1x and R 1y are hydrogen atoms), In the combination of R2 , R4 and R5, is R2 , R4 and R5 all hydrogen atoms?
  • R2 , R4 and R5 is a methyl group in which a halogen atom, a methoxy group or one hydrogen atom may be substituted with a hydroxy group, and the other two are hydrogen atoms.
  • R 3 is a hydrogen atom, a halogen atom, an alkyl group having 1 to 3 carbon atoms in which 1 to 3 arbitrary hydrogen atoms may be independently substituted with a hydroxy group or a fluorine atom, and 3-hydroxyoxetane.
  • 3-yl group, hydroxy group, 1 to 3 arbitrary hydrogen atoms may be substituted with fluorine atoms, alkoxy groups with 1 to 3 carbon atoms, methoxycarbonyl groups, -NR 9 R 10 , -CH 2 NR.
  • R 6 and R 7 each independently represent a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, or each of them represents a hydrogen atom or an alkyl group having 1 to 3 carbon atoms.
  • R 6 and R 7 collectively represent ⁇ (CH 2 ) h ⁇ .
  • h represents an integer of 3 to 5, where any one methylene group may be substituted with an oxygen atom, —NH— or —N (CH 3 ) —.
  • R 8 represents a hydrogen atom or an alkyl group having 1 to 3 carbon atoms.
  • R 9 and R 10 each independently represent a hydrogen atom, -COR 15 or an alkylsulfonyl group having 1 to 3 carbon atoms, or R 9 and R 10 collectively represent ⁇ (CH 2 ) n ⁇ .
  • n represents an integer of 3 to 6 and represents R 11 and R 12 collectively represent ⁇ (CH 2 ) m ⁇ .
  • m represents an integer of 3 to 5, where any one methylene group may be substituted with an oxygen atom.
  • Each of R 13 and R 14 has a hydrogen atom, an alkyl group having 1 to 5 carbon atoms, a 2-hydroxyethyl group, and an arbitrary carbon atom having 1 carbon atom substituted with an oxygen atom. Alternatively, it represents a cycloalkyl group of 4, or a methyl group in which any one carbon atom is substituted with a cycloalkyl group having 3 or 4 carbon atoms, which may be substituted with a nitrogen atom or an oxygen atom.
  • one or two arbitrary hydrogen atoms are a fluorine atom, a methyl group, a hydroxy group or a methoxy group, or one arbitrary CH two group is an oxygen atom and a nitrogen atom.
  • R 16 represents a hydrogen atom or an alkyl group having 1 to 5 carbon atoms.
  • R v represents a hydrogen atom, a methyl group in which one arbitrary hydrogen atom may be substituted with a hydroxy group or a methoxycarbonyl group, or a methoxycarbonyl group.
  • R w represents a hydrogen atom, a methyl group, a hydroxymethyl group or a methoxycarbonyl group (where 2-phenyl-1,2,3,4-tetrahydroquinoline and 3-phenyl-1,2,3,4-tetrahydro). (Excluding quinoline). ]
  • the tetrahydroquinoline derivative (I) which is the active ingredient of the drug of the present invention or a pharmacologically acceptable salt thereof
  • the tetrahydroquinoline derivative described in [1] above or a pharmacologically acceptable salt thereof is used. It is a new compound.
  • the tetrahydroquinoline derivative described in [1] or a pharmacologically acceptable salt thereof is included in the tetrahydroquinoline derivative (I) or a pharmacologically acceptable salt thereof.
  • Halogen atom means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.
  • Alkyl group having 1 to 3 carbon atoms means a methyl group, an ethyl group, a propyl group or an isopropyl group.
  • alkyl group having 1 to 5 carbon atoms means a linear or branched hydrocarbon group having 1 to 5 carbon atoms, for example, a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, and the like. Examples thereof include an isobutyl group, a sec-butyl group, a tert-butyl group, a pentyl group, an isopentyl group, a sec-pentyl group, a tert-pentyl group or a neopentyl group.
  • alkyl group having 1 to 3 carbon atoms in which any 1 to 3 arbitrary hydrogen atoms may be independently substituted with a hydroxy group or a fluorine atom is the above-mentioned "alkyl group having 1 to 3 carbon atoms".
  • 1 to 3 of "" means a group in which any hydrogen atom may be independently substituted with a hydroxy group or a fluorine atom, for example, a methyl group, a hydroxymethyl group, an ethyl group, or 1-hydroxy.
  • alkyl group having 1 to 3 carbon atoms in which any 1 to 3 arbitrary hydrogen atoms may be substituted with a fluorine atom is 1 to 3 of the above-mentioned "alkyl group having 1 to 3 carbon atoms”.
  • any hydrogen atom may be substituted with a fluorine atom, for example, a methyl group, a fluoromethyl group, a difluoromethyl group, a trifluoromethyl group, an ethyl group, a 1,1-difluoroethyl group, 2, 2,2-Trifluoroethyl group, propyl group, 1,1-difluoropropyl group, 2,2-difluoropropyl group, 3,3,3-trifluoropropyl group, isopropyl group, 2-fluoropropane-2-yl Examples include a group or a 1,1,1-trifluoropropane-2-yl group.
  • alkyl group having 1 to 3 carbon atoms in which 1 to 3 arbitrary hydrogen atoms are substituted with a fluorine atom is any 1 to 3 arbitrary groups of the above "alkyl group having 1 to 3 carbon atoms". It means a group in which a hydrogen atom is substituted with a fluorine atom, for example, a fluoromethyl group, a difluoromethyl group, a trifluoromethyl group, a 1,1-difluoroethyl group, a 2,2,2-trifluoroethyl group, 1 , 1-difluoropropyl group, 2,2-difluoropropyl group, 3,3,3-trifluoropropyl group, 2-fluoropropane-2-yl group or 1,1,1-trifluoropropane-2-yl group Can be mentioned.
  • alkyl group having 1 to 3 carbon atoms in which one arbitrary hydrogen atom may be substituted with a hydroxy group is one arbitrary hydrogen atom of the above-mentioned "alkyl group having 1 to 3 carbon atoms".
  • Means a group that may be substituted with a hydroxy group for example, a methyl group, a hydroxymethyl group, an ethyl group, a 1-hydroxyethyl group, a 2-hydroxyethyl group, a propyl group, a 1-hydroxypropyl group, 2-.
  • Examples thereof include a hydroxypropyl group, a 3-hydroxypropyl group, an isopropyl group, a 2-hydroxypropane-2-yl group or a 1-hydroxypropane-2-yl group.
  • alkyl group having 1 to 3 carbon atoms in which one arbitrary hydrogen atom is substituted with a hydroxy group means that one arbitrary hydrogen atom of the above “alkyl group having 1 to 3 carbon atoms” is hydroxy. It means a group substituted with a group, for example, hydroxymethyl group, 1-hydroxyethyl group, 2-hydroxyethyl group, 1-hydroxypropyl group, 2-hydroxypropyl group, 3-hydroxypropyl group, 2-hydroxy. Examples thereof include a propane-2-yl group or a 1-hydroxypropane-2-yl group.
  • a methyl group in which one hydrogen atom may be substituted with a hydroxy group means a methyl group or a hydroxymethyl group.
  • alkoxy group having 1 to 3 carbon atoms means a methoxy group, an ethoxy group, a propoxy group or an isopropoxy group.
  • alkoxy group having 1 to 5 carbon atoms means a monovalent substituent in which a linear or branched hydrocarbon group having 1 to 5 carbon atoms is bonded to an oxygen atom, for example, a methoxy group or an ethoxy group.
  • alkoxy group having 1 to 3 carbon atoms in which any 1 to 3 arbitrary hydrogen atoms may be substituted with a fluorine atom is 1 to 3 of the above-mentioned "alkoxy group having 1 to 3 carbon atoms".
  • any hydrogen atom may be substituted with a fluorine atom, for example, a methoxy group, a fluoromethoxy group, a difluoromethoxy group, a trifluoromethoxy group, an ethoxy group, a 1,1-difluoroethoxy group, 2, 2,2-Trifluoroethoxy group, propoxy group, 1,1-difluoropropoxy group, 2,2-difluoropropoxy group, 3,3,3-trifluoropropoxy group, isopropoxy group, (2-fluoropropane-2) -Il) oxy group or (1,1,1-trifluoropropane-2-yl) oxy group can be mentioned.
  • a fluorine atom for example, a methoxy group, a fluoromethoxy group, a difluoromethoxy group, a trifluoromethoxy group, an ethoxy group, a 1,1-difluoroethoxy group, 2, 2,2-Trifluor
  • a methoxy group in which 1 to 3 arbitrary hydrogen atoms are substituted with a fluorine atom means a fluoromethoxy group, a difluoromethoxy group or a trifluoromethoxy group.
  • the "methoxy group in which 1 to 3 arbitrary hydrogen atoms may be substituted with a fluorine atom” is the above-mentioned "methoxy group in which 1 to 3 arbitrary hydrogen atoms are substituted with a fluorine atom” or It means a methoxy group.
  • alkylsulfonyl group having 1 to 3 carbon atoms means a methylsulfonyl group, an ethylsulfonyl group, a propylsulfonyl group or an isopropylsulfonyl group.
  • aryl group means a monocyclic or bicyclic aromatic hydrocarbon group, and examples thereof include a phenyl group or a naphthyl group (1-naphthyl group or 2-naphthyl group).
  • a 5- or 6-membered ring heteroaryl group containing 1 or 2 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom means a nitrogen atom, an oxygen atom and a sulfur atom in addition to a carbon atom as a constituent atom of the ring. It means a 5- or 6-membered monocyclic aromatic heterocyclic group containing 1 or 2 heteroatoms selected from, for example, a frill group (for example, 2-frill group or 3-frill group), a thienyl group.
  • 2-thienyl group or 3-thienyl group pyrrolyl group (eg, 1-pyrrolyl group, 2-pyrrolyl group or 3-pyrrrolyl group), imidazolyl group (eg, 1-imidazolyl group, 2-imidazolyl group, etc.) 4-imidazolyl group or 5-imidazolyl group), pyrazolyl group (eg, 1-pyrazolyl group, 3-pyrazolyl group or 4-pyrazolyl group), thiazolyl group (eg, 2-thiazolyl group, 4-thiazolyl group or 5-thiazolyl group).
  • pyrrolyl group eg, 1-pyrrolyl group, 2-pyrrolyl group or 3-pyrrrolyl group
  • imidazolyl group eg, 1-imidazolyl group, 2-imidazolyl group, etc.
  • 4-imidazolyl group or 5-imidazolyl group pyrazolyl group
  • pyrazolyl group eg, 1-pyrazoly
  • isothiazolyl group eg, 3-isothiazolyl group, 4-isothiazolyl group or 5-isothiazolyl group
  • oxazolyl group eg, 2-oxazolyl group, 4-oxazolyl group or 5-oxazolyl group
  • isooxazolyl group eg, for example.
  • pyridyl group eg, 2-pyridyl group, 3-pyridyl group or 4-pyridyl group
  • pyrimidinyl group eg, 2-pyrimidinyl group, 4-pyrimidinyl.
  • Examples include a 5-pyrimidinyl group or a 6-pyrimidinyl group), a pyrariainyl group (eg, 3-pyridazinyl group or 4-pyridazinyl group), and a pyrazinyl group (eg, 2-pyramidinyl group).
  • the "5- and 6-membered lactam ring” means a pyrrolidine-2-one ring and a piperidine-2-one ring.
  • 5 and 6-membered ring-saturated heterocycles containing 1 or 2 oxygen atoms as ring constituent atoms are 5 and 6-membered ring containing 1 or 2 oxygen atoms in addition to carbon atoms as ring constituent atoms.
  • a monocyclic saturated heterocycle of, for example, a tetrahydrofuran ring, a 1,3-dioxolan ring, a tetrahydro-2H-pyran ring, a 1,2-dioxane ring, a 1,3-dioxane ring and a 1,4-
  • the "group” is selected from the group consisting of a phenyl group and the above-mentioned “5- and 6-membered lactam rings” and the above-mentioned "5- and 6-membered ring saturated heterocycle containing 1 or 2 oxygen atoms as constituent atoms of the ring".
  • the "fused ring group obtained by condensing a phenyl group and one ring selected from the group consisting of pyrrolidine-2-one, piperidine-2-one and 1,3-dioxolane” is, for example, 3-oxoisoindrin.
  • R2 , R4 and R5 is a methyl group in which a halogen atom, a methoxy group or one hydrogen atom may be substituted with a hydroxy group, and the other two are hydrogen atoms.
  • R 2 and R 4 are methyl groups, one of which may be substituted with a fluorine atom, a chlorine atom, a methoxy group or one hydrogen atom with a hydroxy group, and the other and R 5 are hydrogen atoms.
  • R 2 is a methyl group in which a fluorine atom, a chlorine atom, a methoxy group or one hydrogen atom may be substituted with a hydroxy group
  • both R 4 and R 5 are hydrogen atoms
  • R 4 means a methyl group in which a fluorine atom, a chlorine atom, a methoxy group or one hydrogen atom may be substituted with a hydroxy group
  • both R 2 and R 5 are hydrogen atoms.
  • R 6 and R 7 together represent- (CH 2 ) h- , where h represents an integer of 3-5, where any one methylene group is the oxygen atom, -NH.
  • R 11 and R 12 together represent- (CH 2 ) m- , where m represents an integer of 3-5, where any one methylene group is substituted with an oxygen atom.
  • R 13 and R 14 collectively represent one arbitrary hydrogen atom may be substituted with a hydroxy group- (CH 2 ) k- , and k represents 3 or 4".
  • R 13 and R 14 have one or two arbitrary hydrogen atoms as a fluorine atom, a methyl group, a hydroxy group or a methoxy group, or one arbitrary CH two group as an oxygen atom and nitrogen. Represents an atom or -may be substituted with -CONH-- (CH 2 ) k- , where k represents an integer of 3-5 "means the nitrogen atom to which R 13 and R 14 are attached. Together, one or two arbitrary hydrogen atoms may be substituted with a fluorine atom, a methyl group, a hydroxy group or a methoxy group, or one arbitrary CH 2 group may be an oxygen atom, a nitrogen atom or-.
  • azetidine ring in which one arbitrary hydrogen atom may be substituted with a hydroxy group together with the nitrogen atom to which R 13 and R 14 are bonded is, for example, an azetidine ring or 3-hydroxy azetidine. Ring is mentioned.
  • Azetidine ring in which two arbitrary hydrogen atoms may be substituted with a methyl group or a fluorine atom or one arbitrary hydrogen atom may be substituted with a hydroxy group or a methoxy group means an azetidine ring, 2,2-dimethylazeti. Atomic ring, 2,3-dimethylazetidine ring, 2,4-dimethylazetidine ring, 3,3-dimethylazetidine ring, 3,3-difluoroazetidine ring, 3-hydroxyazetidine ring or 3-methoxyazeti. Gin ring can be mentioned.
  • cycloalkyl group having 3 or 4 carbon atoms in which any one carbon atom may be substituted with an oxygen atom is, for example, a cyclopropyl group, a cyclobutyl group, an oxylan-2-yl group or an oxetane-3. -Il group is mentioned.
  • methyl group in which any one carbon atom is substituted with a cycloalkyl group having 3 or 4 carbon atoms which may be substituted with a nitrogen atom or an oxygen atom is, for example, a cyclopropylmethyl group or a cyclobutyl.
  • examples thereof include a methyl group, an oxylan-2-ylmethyl group, an oxetane-2-ylmethyl, an oxetane-3-ylmethyl, an aziridine-2-ylmethyl, an azetidine-2-ylmethyl group or an azetidine-3-ylmethyl group.
  • methyl group in which any one hydrogen atom may be substituted with a hydroxy group or a methoxycarbonyl group include a methyl group, a hydroxymethyl group or a methoxycarbonylmethyl group.
  • R 1x is a phenyl group (one arbitrary hydrogen atom of the phenyl group is a fluorine atom, a chlorine atom, 1 to 3 arbitrary hydrogen atoms are a fluorine atom, or one arbitrary hydrogen atom is a hydroxy group.
  • a phenyl group (one arbitrary hydrogen atom of the phenyl group is a fluorine atom, a trifluoromethyl group, a hydroxymethyl group, a 2-hydroxypropane-2-yl group, a methoxy group, a trifluoromethoxy group, or a cyano group.
  • One arbitrary hydrogen atom of the phenyl group is replaced with a fluorine atom, a hydroxymethyl group, a trifluoromethoxy group, a cyano group, an aminocarbonyl group, an acetamide group, an aminosulfonyl group, a methylsulfonylamino group or a methylsulfonyl group. It may be).
  • R 1x is a substituted phenyl group, it is preferable that the hydrogen atom at the para position is substituted.
  • R 1x is a phenyl group (any hydrogen atom of the phenyl group is a halogen atom).
  • R 1x is a hydrogen atom and a phenyl group (any hydrogen of the phenyl group).
  • the atom is an alkyl group having 1 to 3 carbon atoms in which any one hydrogen atom is substituted with a hydroxy group, -CONR 6 R 7 , aminosulfonyl group, methylsulfonylamino group, aminosulfonylamino group or 1 carbon atom.
  • one hydrogen atom at the meta position of the phenyl group is substituted with a cyano group, or the hydrogen atom at the para position of the phenyl group is substituted with a trifluoromethoxy group.
  • R 1y is preferably a hydrogen atom, a phenyl group, a 4-hydroxymethylphenyl group, a 4-aminocarbonylphenyl group, a 4-acetamidophenyl group, a 4-aminosulfonylphenyl group, or a 4-methylsulfonylphenyl group.
  • -It is more preferably a hydroxymethylphenyl group, a 4-aminocarbonylphenyl group, a 4-acetamidophenyl group, a 4-aminosulfonylphenyl group or a 4-methylsulfonylphenyl group, and a 4-aminocarbonylphenyl group or a 4-aminosulfonyl group. It is more preferably a phenyl group or a 4-methylsulfonylphenyl group.
  • R 1x and R 1y are not hydrogen atoms.
  • R 1x is a hydrogen atom and R 1y is a substituent other than a hydrogen atom
  • R 1x is a substituent other than a hydrogen atom and R 1y is a hydrogen atom. It is more preferable that R 1x is a substituent other than a hydrogen atom and R 1y is a hydrogen atom.
  • R2 is preferably a hydrogen atom, a fluorine atom, a chlorine atom, a hydroxymethyl group or a methyl group, and more preferably a hydrogen atom.
  • R 3 is an alkyl group having 1 to 3 carbon atoms, a trifluoromethoxy group, and ⁇ CH 2 NR 11 R in which a hydrogen atom, a fluorine atom, a chlorine atom, or any one arbitrary hydrogen atom may be substituted with a hydroxy group. It is preferably 12 or -CH 2 CONR 13 R 14 , more preferably a hydrogen atom, a fluorine atom, a chlorine atom, a methyl group, a hydroxymethyl group, a trifluoromethoxy group or -CH 2 CONR 13 R 14 . It is more preferably a hydrogen atom, a fluorine atom, a chlorine atom or a methyl group.
  • R4 is preferably a hydrogen atom, a fluorine atom, a chlorine atom or a methyl group, and more preferably a hydrogen atom.
  • R 5 is preferably a hydrogen atom.
  • R 6 and R 7 are independently hydrogen atoms or alkyl groups having 1 to 3 carbon atoms, or R 6 and R 7 are piperazine rings and morpholins together with nitrogen atoms bonded to them. It is preferable that a ring, a piperazine ring or an N-methylpiperazine ring is formed, and it is more preferable that both R 6 and R 7 are hydrogen atoms.
  • R 8 is preferably a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, and more preferably a methyl group.
  • R 9 is a hydrogen atom
  • R 10 is a hydrogen atom, -COR 15 or an alkylsulfonyl group having 1 to 3 carbon atoms, or R 9 and R 10 are integrally- (CH). 2 ) n ⁇ , n is preferably 4 or 5, R 9 is a hydrogen atom, and R 10 is more preferably ⁇ COR 15 .
  • R 11 and R 12 are integrally ⁇ (CH 2 ) m ⁇ , where m is 4 or 5 (where any one methylene group may be substituted with an oxygen atom). Is preferable.
  • R 13 is a hydrogen atom or a methyl group
  • R 14 is a hydrogen atom, a methyl group, an ethyl group, an isopropyl group, a tert-butyl group, a 2-hydroxyethyl group, a cyclopropyl group, a cyclobutyl group and an oxetane-3-. It is an yl group, a cyclopropylmethyl group, a cyclobutylmethyl group or an oxetane-3-ylmethyl, or R 13 and R 14 are a pyrrolidine ring, a piperidine ring, a piperazine ring, together with a nitrogen atom bonded to them.
  • a morpholine ring an azetidine ring, a 3,3-dimethylazetidine ring, a 3,3-difluoroazetidine ring, a 3-hydroxyazetidine ring or a 3-methoxyazetidine ring.
  • R 15 is preferably an alkyl group having 1 to 5 carbon atoms, an alkoxy group having 1 to 5 carbon atoms, or —NHR 16 .
  • R 16 is preferably a hydrogen atom or an alkyl group having 1 to 5 carbon atoms.
  • Rv is preferably a hydrogen atom.
  • R w is preferably a hydrogen atom.
  • the tetrahydroquinoline derivative (I) or a pharmaceutically acceptable salt thereof is not only a single stereoisomer but also a mixture of stereoisomers such as a racemic mixture and a diastereomeric mixture (for example, a mirror isomer). (Mixture of) is also included.
  • stereoisomer refers to a compound having the same chemical structure but different arrangement in three-dimensional space, for example, a constitutive isomer, a rotational isomer, a tautovariate, a mirror image isomer or a diastereomer. And so on.
  • the above tetrahydroquinoline derivative (I) may have the following general formulas (I-1) to (I-8).
  • R 1x , R 1y , R 2 , R 3 , R 4 , R 5 , R v and R w are synonymous with the above definitions.
  • any embodiment of the above-mentioned preferable R 1x , R 1y , R 2 to R 16 , R v , R w and the above-mentioned preferable h, k, m, n is selected, and they are used. Can be combined. For example, the following combinations can be mentioned, but the present invention is not limited to the following combinations.
  • R 1x is a phenyl group (one arbitrary hydrogen atom of the phenyl group is a fluorine atom, a chlorine atom, and 1 to 3 arbitrary hydrogen atoms are fluorine atoms.
  • one arbitrary hydrogen atom may be substituted with a hydroxy group, and an alkyl group having 1 to 3 carbon atoms may be substituted.
  • 1 to 3 arbitrary hydrogen atoms may be substituted with a fluorine atom.
  • alkoxy groups 3 alkoxy groups, cyano groups, methoxycarbonyl groups, -CONR 6 R 7 , -NHCOR 8 , aminosulfonyl groups, alkylsulfonylamino groups with 1-3 carbon atoms, aminosulfonylamino groups or alkylsulfonyls with 1-3 carbon atoms. It may be substituted with a group), pyrazolyl group, 1-oxoisoindrin-5-yl group, 2-oxo-1,2,3,4-tetrahydroquinoline-6-yl group or benzo [d] [1.
  • R1y is a hydrogen atom and R 2 is a hydrogen atom
  • R 3 is an alkyl group having 1 to 3 carbon atoms, a methoxy group, -NR 9 R 10 , -CH, in which a hydrogen atom, a fluorine atom, a chlorine atom, or any one hydrogen atom may be substituted with a hydroxy group.
  • 2 NR 11 R 12 or -CH 2 CONR 13 R 14 R4 is a hydrogen atom or a methoxy group.
  • R 5 is a hydrogen atom
  • R 6 and R 7 are independently hydrogen atoms or alkyl groups having 1 to 3 carbon atoms, or R 6 and R 7 are piperazine rings and morpholins together with nitrogen atoms bonded to them. It may form a ring, a piperazine ring or an N-methylpiperazine ring.
  • R 8 is a hydrogen atom or an alkyl group having 1 to 3 carbon atoms
  • R 9 is a hydrogen atom
  • R 10 is a hydrogen atom, ⁇ COR 15 or an alkylsulfonyl group having 1 to 3 carbon atoms.
  • R 9 and R 10 are integrally ⁇ (CH 2 ) n ⁇ , and are n is 4 or 5
  • R 11 and R 12 are integrally- (CH 2 ) m- , and are m is 4 or 5, where any one methylene group may be substituted with an oxygen atom.
  • R 13 is a hydrogen atom or a methyl group
  • R 14 is a hydrogen atom, a methyl group, an ethyl group, an isopropyl group, a tert-butyl group, a 2-hydroxyethyl group, a cyclopropyl group, a cyclobutyl group and an oxetane-3-.
  • An yl group, a cyclopropylmethyl group, a cyclobutylmethyl group or an oxetane-3-ylmethyl, or R 13 and R 14 are a pyrrolidine ring, a piperidine ring, a piperazine ring, together with a nitrogen atom bonded to them. It may form a morpholine ring, an azetidine ring, a 3,3-dimethylazetidine ring, a 3,3-difluoroazetidine ring, a 3-hydroxyazetidine ring or a 3-methoxyazetidine ring.
  • R 15 is an alkyl group having 1 to 5 carbon atoms, an alkoxy group having 1 to 5 carbon atoms, or ⁇ NHR 16 .
  • R 16 is a hydrogen atom or an alkyl group having 1 to 5 carbon atoms.
  • Rv is a hydrogen atom
  • R w is preferably a hydrogen atom (excluding 2-phenyl-1,2,3,4-tetrahydroquinoline).
  • one embodiment includes, for example, the tetrahydroquinoline derivative represented by the following general formula (II-a) or a pharmacologically acceptable salt thereof.
  • A is a hydrogen atom or -CONH 2
  • R 9 and R 10 are independently hydrogen atoms, -COR 15 or an alkylsulfonyl group having 1 to 3 carbon atoms, or R. 9 and R 10 are integrally ⁇ (CH 2 ) n ⁇ , n is an integer of 3 to 6, and R 15 is an alkyl group having 1 to 5 carbon atoms and 1 to 5 carbon atoms. It is an alkoxy group or ⁇ NHR 16 , and R 16 is a hydrogen atom or an alkyl group having 1 to 5 carbon atoms.
  • R 9 is a hydrogen atom
  • R 10 is -COR 15
  • R. 15 is preferably an alkoxy group having 1 to 5 carbon atoms
  • A is a hydrogen atom
  • R 9 is a hydrogen atom
  • R 10 is ⁇ COR 15
  • R 15 is an alkoxy group having 1 to 5 carbon atoms. More preferably, it is a group, where A is a hydrogen atom, R 9 is a hydrogen atom, R 10 is ⁇ COR 15 , and R 15 is a tert-butoxy group.
  • the above-mentioned tetrahydroquinoline derivative (II-a) or a pharmacologically acceptable salt thereof contains the above-mentioned tetrahydroquinoline derivative (II-a) or a pharmacologically acceptable salt thereof as an active ingredient. It can be used as a pharmaceutical product, and more preferably, it can be used as a pharmaceutical product for treating or preventing a disease, disorder or syndrome associated with inhibition of ferrotosis.
  • the tetrahydroquinoline derivative (II-a) or a pharmacologically acceptable salt thereof contains the tetrahydroquinoline derivative (II-a) or a pharmacologically acceptable salt thereof as an active ingredient. It can be used as a ferrotosis inhibitor.
  • one embodiment includes, for example, a tetrahydroquinoline derivative represented by the following general formula (II-b) or a pharmacologically acceptable salt thereof.
  • R1y is a phenyl group, 4-hydroxymethylphenyl group, 4-aminocarbonylphenyl group, 4-acetamidophenyl group, 4-aminosulfonylphenyl group, 4-methylsulfonylphenyl or 3-pyridyl group.
  • R 3 is a hydrogen atom or a halogen atom
  • R 4 is a hydrogen atom or a halogen atom (excluding 3-phenyl-1,2,3,4-tetrahydroquinoline).
  • R1y is a 4-hydroxymethylphenyl group, a 4-aminocarbonylphenyl group, 4-acetamidophenyl group, 4-aminosulfonylphenyl group or 4-methylsulfonylphenyl group
  • R 3 is a hydrogen atom, a fluorine atom or a chlorine atom
  • R 4 is a hydrogen atom, a fluorine atom or a chlorine atom.
  • R 1y is preferably a 4-aminocarbonylphenyl group, a 4-aminosulfonylphenyl group or a 4-methylsulfonylphenyl group, R 3 is a hydrogen atom, and R 4 is a hydrogen atom. Is more preferable.
  • the above-mentioned tetrahydroquinoline derivative (II-b) or a pharmacologically acceptable salt thereof contains the above-mentioned tetrahydroquinoline derivative (II-b) or a pharmacologically acceptable salt thereof as an active ingredient. It can be used as a pharmaceutical product, and more preferably, it can be used as a pharmaceutical product for treating or preventing a disease, disorder or syndrome associated with inhibition of ferrotosis.
  • the above-mentioned tetrahydroquinoline derivative (II-b) or a pharmacologically acceptable salt thereof contains the above-mentioned tetrahydroquinoline derivative (II-b) or a pharmacologically acceptable salt thereof as an active ingredient. It can be used as a ferrotosis inhibitor.
  • the compounds listed in Tables 1-1 to 1-7 also include their stereoisomers and solvates thereof, and pharmacologically acceptable salts thereof and mixtures thereof.
  • the present invention includes the above-mentioned prodrug of the tetrahydroquinoline derivative (I).
  • the prodrug of the tetrahydroquinoline derivative (I) is a compound that is enzymatically or chemically converted into the tetrahydroquinoline derivative (I) in vivo.
  • the activity body of the above-mentioned tetrahydroquinoline derivative (I) prodrug is the above-mentioned tetrahydroquinoline derivative (I), but the above-mentioned tetrahydroquinoline derivative (I) prodrug itself may have activity.
  • Examples of the group forming the prodrug of the above tetrahydroquinoline derivative (I) include publicly known documents (for example, "Development of Pharmaceuticals", Hirokawa Shoten, 1990, Vol. 7, p.163-198 and Progress in Medicine, No. The basis described in Volume 5, 1985, p. 2157-2161) can be mentioned.
  • Examples of the "pharmacologically acceptable salt" of the tetrahydroquinoline derivative (I) include inorganic salts such as hydrochloride, sulfate, nitrate, hydrobromide, hydroiodide or phosphate.
  • the above-mentioned tetrahydroquinoline derivative (I) may be crystalline, and may be included in the above-mentioned tetrahydroquinoline derivative (I) regardless of whether the crystal form is single or a crystalline form mixture.
  • the tetrahydroquinoline derivative (I) described above may be a pharmaceutically acceptable co-crystal or co-crystal salt.
  • the co-crystal or co-crystal salt is unique to two or more at room temperature, each having different physical properties (eg, structure, melting point, heat of fusion, hygroscopicity, solubility or stability). It means a crystalline substance composed of a solid.
  • the co-crystal or co-crystal salt can be produced according to a known co-crystallization method.
  • tetrahydroquinoline derivative (I) or a pharmacologically acceptable salt thereof may be anhydrous or may form a solvate such as hydrate.
  • the above-mentioned tetrahydroquinoline derivative (I) or a pharmacologically acceptable salt thereof can be used as a solvate such as a hydrate by a known method.
  • a known method for example, the above tetrahydroquinoline derivative (I) or a pharmaceutically acceptable salt thereof is used in water, another solvent (for example, an alcohol solvent such as methanol, ethanol or n-propanol, N). , N-dimethylformamide (hereinafter, DMF), dimethyl sulfoxide (hereinafter, DMSO)) or a method of treating with a mixed solvent thereof.
  • DMF N-dimethylformamide
  • DMSO dimethyl sulfoxide
  • the above tetrahydroquinoline derivative (I) may be labeled with one or more isotopes, and the labeled isotopes include, for example, 2H , 3H , 13C , 14C , 15N , 15 Examples include O, 17 O, 18 O and / or 125 I.
  • the above-mentioned tetrahydroquinoline derivative (I) can be produced by an appropriate method based on the characteristics derived from the basic skeleton and the type of substituent.
  • the starting materials and reagents used for the production of these compounds can be generally purchased or can be produced by a known method.
  • the above-mentioned tetrahydroquinoline derivative (I) and the intermediates and starting materials used for its production can be isolated and purified by known means.
  • Known means for isolation and purification include, for example, solvent extraction, recrystallization or chromatography.
  • each isomer can be obtained as a single compound by a known method or a method similar thereto.
  • Known methods include, for example, crystallization, enzymatic splitting or chiral chromatography.
  • the following is an example of a general method for producing the above tetrahydroquinoline derivative (I).
  • the compound in the following scheme includes the case of forming a salt, and as such a salt, for example, the same as the salt in the above-mentioned tetrahydroquinoline derivative (I) is used.
  • the production method of the present invention is not limited to the examples shown below.
  • R 1y , R v , and R w are all hydrogen atoms
  • R 3 is a hydrogen atom, a halogen atom, and 1 to 3 arbitrary hydrogen atoms, respectively.
  • the tetrahydroquinoline derivative (IA) which is a group or a methoxycarbonyl group can be obtained, for example, by the method described in Scheme 1.
  • X represents a halogen atom
  • R 3a is a hydrogen atom, a halogen atom, or 1 to 3 arbitrary hydrogen atoms, each of which may be independently substituted with a hydroxy group or a fluorine atom.
  • the quinoline derivative (IX) can be obtained by a coupling reaction between the 2-haloquinoline derivative (III) and the boronic acid derivative (IV) in the presence of a metal catalyst and a base.
  • the amount of the boronic acid derivative (IV) used in the coupling reaction is preferably 0.5 to 10 equivalents, more preferably 0.8 to 4 equivalents, relative to the 2-haloquinoline derivative (III).
  • metal catalyst used in the coupling reaction examples include 1,1'-bis (diphenylphosphino) ferrosendichloropalladium (II) dichloromethane adduct, palladium (II) chloride, palladium (II) acetate, and bis (dibenzylideneacetone).
  • the amount of the metal catalyst used in the coupling reaction is preferably 0.01 to 5 equivalents, more preferably 0.025 to 1 equivalent with respect to the 2-haloquinoline derivative (III).
  • the coupling reaction may further use a ligand.
  • ligand examples include triphenylphosphine, tert-butylphosphine or 2,2'-bis (diphenylphosphine) -1,1'-binaphthyl.
  • Examples of the base used for the coupling reaction include organic bases such as triethylamine or N, N-diisopropylethylamine, inorganic bases such as sodium carbonate, potassium carbonate or cesium carbonate, and lithium such as lithium hexamethyldisilazide or lithium diisopropylamide.
  • organic bases such as triethylamine or N, N-diisopropylethylamine
  • inorganic bases such as sodium carbonate, potassium carbonate or cesium carbonate
  • lithium such as lithium hexamethyldisilazide or lithium diisopropylamide.
  • metal alkoxides such as amide, sodium tert-butoxide or potassium tert-butoxide or mixtures thereof, but inorganic bases such as sodium carbonate, potassium carbonate or cesium carbonate are preferred.
  • the amount of the base used in the coupling reaction is preferably 0.5 to 10 equivalents with respect to the 2-haloquinoline derivative (III), more preferably 1 to 4 equivalents.
  • the reaction solvent used for the coupling reaction is appropriately selected depending on the type of the reagent used and the like, but is not particularly limited as long as it does not inhibit the reaction, and is not particularly limited, for example, tetrahydrofuran (hereinafter referred to as THF), 1,4-.
  • Ether-based solvents such as dioxane or 1,2-dimethoxyethane (hereinafter, DME), nitrile-based solvents such as acetonitrile or propionitrile, aromatic hydrocarbon-based solvents such as benzene or toluene, DMF, N, N-dimethylacetamide.
  • DMA aprotonic polar solvent
  • water or a mixed solvent thereof can be mentioned, but an ether solvent such as THF, 1,4-dioxane or DME, and an aproton such as DMF, DMA or DMSO can be mentioned.
  • a sex polar solvent or water and a mixed solvent thereof are preferable.
  • the reaction temperature of the coupling reaction is preferably 0 to 200 ° C, more preferably 50 to 150 ° C.
  • the reaction time of the coupling reaction is appropriately selected according to conditions such as the reaction temperature, but is preferably 1 to 30 hours.
  • the 2-haloquinoline derivative (III) and the boronic acid derivative (IV) used in the coupling reaction can be purchased, or can be produced by a known method or a method similar thereto.
  • the quinoline derivative (IX) can be obtained by a cycloaddition reaction between a 2-aminobenzyl alcohol derivative (V) and a ketone derivative (VI) in the presence of a base.
  • a cycloaddition reaction between a 2-aminobenzyl alcohol derivative (V) and a ketone derivative (VI) in the presence of a base.
  • it can be carried out according to the method described in (Tetrahedron Letters, 2008, pp. 6893-6895) or a method similar thereto.
  • the amount of the ketone derivative (VI) used in the cycloaddition reaction is preferably 0.5 to 10 equivalents, more preferably 0.8 to 5 equivalents, relative to the 2-aminobenzyl alcohol derivative (V).
  • Examples of the base used for the addition cyclization reaction include inorganic bases such as sodium hydroxide, potassium hydroxide or cesium hydroxide, metal alkoxides such as sodium ethoxydo, sodium tert-butoxide or potassium tert-butoxide, and sodium hydride.
  • inorganic bases such as sodium hydroxide, potassium hydroxide or cesium hydroxide
  • metal alkoxides such as sodium ethoxydo, sodium tert-butoxide or potassium tert-butoxide
  • sodium hydride examples include metal hydride compounds such as potassium hydride or calcium hydride, or mixtures thereof, but metal alkoxides such as sodium ethoxydo, sodium tert-butoxide or potassium tert-butoxide are preferred.
  • the amount of the base used in the cycloaddition reaction is preferably 0.5 to 10 equivalents with respect to the 2-aminobenzyl alcohol derivative (V), more preferably 1 to 3 equivalents.
  • the reaction solvent used for the addition cyclization reaction is appropriately selected depending on the type of the reagent used and the like, but is not particularly limited as long as it does not inhibit the reaction, and is not particularly limited, for example, THF, 1,4-dioxane, DME and the like.
  • examples include ether solvents, aromatic hydrocarbon solvents such as benzene or toluene, aprotonic polar solvents such as DMF, DMA or DMSO, or mixed solvents thereof, such as THF, 1,4-dioxane or DME. Ethereal solvents are preferred.
  • the reaction temperature of the addition cyclization reaction is preferably 0 to 200 ° C, more preferably 50 to 150 ° C.
  • the reaction time of the addition cyclization reaction is appropriately selected according to conditions such as the reaction temperature, but is preferably 1 to 24 hours.
  • the 2-aminobenzyl alcohol derivative (V) and the ketone derivative (VI) used in the cycloaddition reaction can be purchased, or can be produced by a known method or a method similar thereto.
  • the quinoline derivative (IX) is an oxidative cyclization reaction between an aniline derivative (VII) and an allyl alcohol derivative (VIII-a) or an ⁇ , ⁇ unsaturated aldehyde derivative (VIII-b) in an oxygen atmosphere and in the presence of a metal catalyst.
  • a metal catalyst can be obtained by For example, it can be carried out according to the method described in (RSC Advances, 2017, pp. 36242-36245) or a method similar thereto.
  • the amount of the allyl alcohol derivative (VIII-a) or ⁇ , ⁇ unsaturated aldehyde derivative (VIII-b) used in the oxidative cyclization reaction is preferably 0.5 to 10 equivalents with respect to the aniline derivative (VII), and is 0. .8 to 2 equivalents are more preferred.
  • Examples of the metal catalyst used in the oxidative cyclization reaction include palladium (II) acetate, palladium (II) trifluoroacetate, palladium (II) chloride and palladium (II) dichlorobis (acethal), but palladium acetate (II). II) is preferable.
  • the amount of the metal catalyst used in the oxidative cyclization reaction is preferably 0.01 to 5 equivalents, more preferably 0.025 to 1 equivalent with respect to the aniline derivative (VII).
  • the pressure of oxygen used in the oxidative cyclization reaction is preferably about 1 to about 20 atm, more preferably about 1 to about 5 atm.
  • the reaction solvent used for the oxidative cyclization reaction is appropriately selected depending on the type of the reagent used and the like, but is not particularly limited as long as it does not inhibit the reaction, and is not particularly limited, for example, THF, 1,4-dioxane or DME.
  • examples thereof include ether solvents such as, aromatic hydrocarbon solvents such as benzene and toluene, aprotic polar solvents such as DMF, DMA and DMSO, and mixed solvents thereof, which are aprotonic such as DMF, DMA or DMSO.
  • Polar solvents are preferred.
  • the reaction temperature of the oxidative cyclization reaction is preferably 0 to 300 ° C, more preferably 70 to 200 ° C.
  • the reaction time of the oxidative cyclization reaction is appropriately selected according to conditions such as the reaction temperature, but is preferably 1 to 24 hours.
  • the aniline derivative (VII), allyl alcohol derivative (VIII-a) and ⁇ , ⁇ unsaturated aldehyde derivative (VIII-b) used in the oxidative cyclization reaction can be purchased or are known methods or the like. It can be manufactured by the method.
  • the tetrahydroquinoline derivative (IA) can be obtained by hydrogenating the quinoline derivative (IX) in a hydrogen atmosphere and in the presence of a metal catalyst. Alternatively, it can be obtained by a hydrogen transfer reduction reaction between a 1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylic acid ester derivative and a quinoline derivative (IX).
  • metal catalyst used in the hydrogenation reaction examples include palladium such as palladium carbon, palladium (II) hydroxide carbon or palladium (II) oxide, nickels such as a developed nickel catalyst, platinum (IV) oxide or platinum carbon and the like. Platinums, rhodiums such as rhodium carbon, and the like can be mentioned, but platinum oxide (IV) is preferable.
  • the amount of the metal catalyst used in the hydrogenation reaction is preferably 0.001 to 1 equivalent, more preferably 0.01 to 0.5 equivalent, relative to the quinoline derivative (IX).
  • the pressure of hydrogen used in the hydrogenation reaction is preferably about 1 to about 30 atm, more preferably about 1 to about 10 atm.
  • the reaction solvent used for the hydrogenation reaction is appropriately selected depending on the type of reagent used and the like, but is not particularly limited as long as it does not inhibit the reaction, and is not particularly limited, for example, methanol, ethanol, isopropyl alcohol or tert-butyl alcohol.
  • Alcohol-based solvents such as, aromatic hydrocarbon-based solvents such as toluene or xylene, chlorine-based solvents such as dichloromethane, chloroform or 1,2-dichloroethane, ether-based solvents such as diethyl ether, THF, DME or 1,4-dioxane.
  • Ester solvent such as ethyl acetate or propyl acetate, aprotonic polar solvent such as DMF, DMA or DMSO, carboxylic acid solvent such as formic acid or acetic acid, water or a mixed solvent thereof, but methanol, ethanol, etc.
  • a mixed solvent of an alcohol solvent such as isopropyl alcohol or tert-butyl alcohol and a carboxylic acid solvent such as formic acid or acetic acid is preferable.
  • the reaction temperature of the hydrogenation reaction is preferably 0 to 200 ° C, more preferably 10 to 100 ° C.
  • the reaction time of the hydrogenation reaction is appropriately selected depending on the conditions such as the reaction temperature, but 0.5 to 40 hours is preferable.
  • Examples of the 1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylic acid ester derivative used for the hydrogen transfer reduction reaction include 2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylic acid.
  • the amount of the 1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylic acid ester derivative used in the hydrogen transfer reduction reaction is preferably 1 to 10 equivalents with respect to the quinoline derivative (IX), 1.7 to 1. 3 equivalents are more preferred.
  • the reaction solvent used for the hydrogen transfer reduction reaction is appropriately selected depending on the type of reagent used and the like, but is not particularly limited as long as it does not inhibit the reaction, and is not particularly limited, for example, methanol, ethanol, isopropyl alcohol or tert-butyl.
  • Alcohol-based solvent such as alcohol, aromatic hydrocarbon-based solvent such as toluene or xylene, chlorine-based solvent such as dichloromethane, chloroform or 1,2-dichloroethane, ether-based solvent such as diethyl ether, THF, DME or 1,4-dioxane.
  • Examples thereof include a solvent, an ester solvent such as ethyl acetate or propyl acetate, an aprotonic polar solvent such as DMF, DMA or DMSO, or a mixed solvent thereof, and a chlorine solvent such as dichloromethane, chloroform or 1,2-dichloroethane or Ether-based solvents such as diethyl ether, THF, DME or 1,4-dioxane are preferred.
  • the reaction temperature of the hydrogen transfer reduction reaction is preferably 0 to 100 ° C, more preferably 10 to 50 ° C.
  • the reaction time of the hydrogen transfer reduction reaction is appropriately selected according to conditions such as the reaction temperature, but is preferably 1 to 24 hours.
  • the aminoquinoline derivative (XI) can be obtained by a coupling reaction between the 6-haloquinoline derivative (IX-a) and the secondary amine derivative (X) in the presence of a metal catalyst and a base.
  • the amount of the secondary amine derivative (X) used in the coupling reaction is preferably 0.5 to 20 equivalents, more preferably 0.8 to 10 equivalents, relative to the 6-haloquinoline derivative (IX-a).
  • Examples of the metal catalyst used in the coupling reaction include 1,1′-bis (diphenylphosphino) ferrosendichloropalladium (II) dichloromethane adduct, palladium (II) chloride, palladium (II) acetate, and bis (dibenzylideneacetone).
  • Palladium (0), tris (dibenzylideneacetone) dipalladium (0), tetrakistriphenylphosphine palladium (0) or dichlorobistriphenylphosphine palladium (0), although palladium (II) acetate is preferred.
  • the amount of the metal catalyst used in the coupling reaction is preferably 0.001 to 5 equivalents, more preferably 0.02 to 0.5 equivalents, relative to the 6-haloquinoline derivative (IX-a).
  • the coupling reaction may further use a ligand.
  • ligand examples include triphenylphosphine, tert-butylphosphine, 2,2'-bis (diphenylphosphine) -1,1'-binaphthyl, 2- (dicyclohexylphosphine) -2', 4'. , 6'-triisopropyl-1,1'-biphenyl or 4,5-bis (diphenylphosphino) -9,9-dimethylxanthene and the like.
  • the amount of the ligand is preferably 0.001 to 5 equivalents, more preferably 0.02 to 1 equivalent with respect to the 6-haloquinoline derivative (IX-a).
  • Examples of the base used for the coupling reaction include organic bases such as triethylamine or N, N-diisopropylethylamine, inorganic bases such as sodium carbonate, potassium carbonate or cesium carbonate, and lithium such as lithium hexamethyldisilazide or lithium diisopropylamide.
  • organic bases such as triethylamine or N, N-diisopropylethylamine
  • inorganic bases such as sodium carbonate, potassium carbonate or cesium carbonate
  • lithium such as lithium hexamethyldisilazide or lithium diisopropylamide.
  • metal alkoxides such as amide, sodium tert-butoxide or potassium tert-butoxide or mixtures thereof, but inorganic bases such as sodium carbonate, potassium carbonate or cesium carbonate are preferred.
  • the amount of the base used in the coupling reaction is preferably 0.8 to 10 equivalents, more preferably 1 to 5 equivalents, relative to the 6-haloquinoline derivative (IX-a).
  • the reaction solvent used for the coupling reaction is appropriately selected depending on the type of reagent used and the like, but is not particularly limited as long as it does not inhibit the reaction, and is not particularly limited, for example, methanol, ethanol, isopropyl alcohol or tert-butyl alcohol.
  • Alcohol-based solvents such as THF, ether solvents such as 1,4-dioxane or DME, aromatic hydrocarbon solvents such as benzene or toluene, nitrile solvents such as acetonitrile or propionitrile, DMF, DMA or DMSO and the like.
  • Examples thereof include an aprotonic polar solvent, a chlorine-based solvent such as dichloromethane, chloroform or 1,2-dichloroethane, or a mixed solvent thereof, and an ether-based solvent such as THF, 1,4-dioxane or DME is preferable.
  • aprotonic polar solvent a chlorine-based solvent such as dichloromethane, chloroform or 1,2-dichloroethane, or a mixed solvent thereof
  • an ether-based solvent such as THF, 1,4-dioxane or DME is preferable.
  • the reaction temperature of the coupling reaction is preferably 0 to 200 ° C, more preferably 50 to 150 ° C.
  • the reaction time of the coupling reaction is appropriately selected according to conditions such as the reaction temperature, but is preferably 1 to 30 hours.
  • the 6-haloquinoline derivative (IX-a) used in the coupling reaction can be purchased, or can be produced by the method described in Steps 1-1 to 1-3, a known method, or a method similar thereto. Can be done.
  • the secondary amine derivative (X) used in the coupling reaction can be purchased, or can be produced by a known method or a method similar thereto.
  • Step 2-2 The tetrahydroquinoline derivative (Ib) can be obtained by a hydrogenation reaction or a hydrogen transfer reduction reaction of the aminoquinoline derivative (XI).
  • the selection conditions for the reagent, catalyst, hydrogen pressure, reaction solvent, and reaction temperature in this step are the same as in steps 1-4.
  • R 1y , R v and R w are all hydrogen atoms
  • R 3 is NR 9 R 10
  • R 9 is a hydrogen atom
  • R 10 is ⁇ COR 15
  • R 15 is an alkoxy group having 1 to 5 carbon atoms
  • the tetrahydroquinoline derivative (Ic) can be obtained, for example, by the method described in Scheme 3.
  • Y represents an alkyl group having 1 to 5 carbon atoms, and each of the other symbols has the same meaning as the above definition.
  • the quinoline-6-carboxylic acid derivative (XII) can be obtained by the hydrolysis reaction of the quinoline-6-carboxylic acid ester derivative (IX-b) in the presence of a base.
  • Examples of the base used for the hydrolysis reaction include lithium hydroxide, potassium hydroxide, sodium hydroxide or sodium tert-butoxide, with potassium hydroxide or sodium hydroxide being preferred.
  • the amount of the base used in the hydrolysis reaction is preferably 0.5 to 100 equivalents, more preferably 0.8 to 30 equivalents, relative to the quinoline-6-carboxylic acid ester derivative (IX-b). ..
  • the reaction solvent used for the hydrolysis reaction is appropriately selected depending on the type of the reagent used, but is not particularly limited as long as it does not inhibit the reaction, and is, for example, an ether solvent such as THF, 1,4-dioxane or DME. Solvents, chlorine-based solvents such as dichloromethane, chloroform or 1,2-dichloroethane, aromatic hydrocarbon-based solvents such as benzene or toluene, aprotonic polar solvents such as DMF, DMA or DMSO, and ketone solvents such as acetone or methyl ethyl ketone. , An alcohol solvent such as methanol, ethanol or 2-propanol, water or a mixed solvent thereof, and a mixed solvent of an alcohol solvent such as methanol, ethanol or 2-propanol and water is preferable.
  • an ether solvent such as THF, 1,4-dioxane or DME.
  • Solvents chlorine-based solvents such as
  • the reaction temperature of the hydrolysis reaction is preferably ⁇ 50 ° C. to 150 ° C., more preferably ⁇ 20 ° C. to 100 ° C.
  • the reaction time of the hydrolysis reaction is appropriately selected according to conditions such as the reaction temperature, but is preferably 1 to 30 hours.
  • the quinoline-6-carboxylic acid ester derivative (IX-b) used in the hydrolysis reaction can be purchased, or the method according to Steps 1-1 to 1-3, a known method or a method similar thereto. Can be manufactured with.
  • the quinoline-6-carbamic acid ester derivative (XIV) is an alcoholic decomposition of the isocyanato derivative produced by the rearrangement reaction of the acid azide produced by using diphenylphosphoryl azide for the quinoline-6-carboxylic acid derivative (XII). It can be obtained by reaction.
  • the amount of diphenylphosphoryl azide used in the rearrangement reaction is preferably 1 to 10 equivalents, more preferably 1 to 3 equivalents, relative to the quinoline-6-carboxylic acid derivative (XII).
  • Examples of the base used for the rearrangement reaction include inorganic bases such as sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, magnesium hydroxide or calcium hydroxide, or organic bases such as triethylamine or N, N-diisopropylethylamine. Examples thereof include an organic base such as triethylamine or N, N-diisopropylethylamine.
  • the amount of the base used in the rearrangement reaction is preferably 1 to 10 equivalents with respect to the quinoline-6-carboxylic acid derivative (XII), and more preferably 1 to 3 equivalents.
  • the reaction solvent used for the rearrangement reaction is appropriately selected depending on the type of the reagent used and the like, but is not particularly limited as long as it does not inhibit the reaction, and is not particularly limited, for example, an ether such as THF, 1,4-dioxane or DME.
  • System solvent ester solvent such as ethyl acetate or propyl acetate, chlorine solvent such as dichloromethane, chloroform or 1,2-dichloroethane, aromatic hydrocarbon solvent such as benzene or toluene, nitrile solvent such as acetonitrile or propionitrile.
  • examples thereof include a solvent, an aprotonic polar solvent such as DMF, DMA or DMSO, or a mixed solvent thereof.
  • alcohols (XIII) used in the alcohol-added decomposition reaction include methanol, ethanol, isopropyl alcohol and tert-butyl alcohol.
  • the amount of alcohols (XIII) used in the alcohol-added decomposition reaction may be 1 to 20 equivalents with respect to the quinoline-6-carboxylic acid derivative (XII), or the reaction solvent may be used instead of the reaction solvent used in the rearrangement reaction. May be used as.
  • the reaction temperature of the rearrangement reaction and the alcohol-added decomposition reaction is preferably 30 to 200 ° C, more preferably 50 to 150 ° C.
  • the reaction time of the rearrangement reaction and the alcohol-added decomposition reaction is appropriately selected depending on the conditions such as the reaction temperature, but is preferably 1 to 30 hours.
  • a quinoline-6-carbamic acid ester derivative (XIV) can be obtained.
  • Examples of the above-mentioned reactive functional group include acid anhydrides, mixed acid anhydrides with chlorocarbonates (eg, methyl chlorocarbonate, ethyl chlorocarbonate, isobutyl chlorocarbonate), symmetric acid anhydrides, and activation with imidazole. Amid is mentioned.
  • Step 3-3 The tetrahydroquinoline derivative (Ic) can be obtained by a hydrogenation reaction or a hydrogen transfer reduction reaction of the quinoline-6-carbamic acid ester derivative (XIV).
  • the selection conditions for the reagent, catalyst, hydrogen pressure, reaction solvent, and reaction temperature in this step are the same as in steps 1-4.
  • R 1y , R v and R w are all hydrogen atoms
  • R 3 is -NR 9 R 10
  • R 9 is a hydrogen atom
  • R 10 is -COR 15 or. It is an alkylsulfonyl group having 1 to 3 carbon atoms
  • R 15 is an alkyl group having 1 to 5 carbon atoms or -NHR 16
  • R 16 is a hydrogen atom and a tetrahydroquinoline which is an alkyl group having 1 to 5 carbon atoms.
  • Derivatives (Id) to (If) can be obtained, for example, by the method described in Scheme 4.
  • L independently represents a leaving group
  • Z represents an alkyl group having 1 to 3 carbon atoms, and each other symbol has the same meaning as the above definition.
  • Examples of the desorbing group represented by L include a halogen atom such as a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, an alkylthio group having 1 to 12 carbon atoms such as a methylthio group, an ethylthio group or a dodecylthio group, and a phenoxy group.
  • a halogen atom such as a fluorine atom, a chlorine atom, a bromine atom or an iodine atom
  • an alkylthio group having 1 to 12 carbon atoms such as a methylthio group, an ethylthio group or a dodecylthio group
  • a phenoxy group such as a halogen atom such as a fluorine atom, a chlorine atom, a bromine atom or an iodine atom
  • alkylsulfonyloxy group such as an aryloxy group, a methanesulfonyloxy group, an ethanesulfonyloxy group or a trifluoromethanesulfonyloxy group may be substituted with a halogen atom, and an alkylsulfonylamino group such as a trifluoromethanesulfonylamino group.
  • alkylsulfonylamino group such as a trifluoromethanesulfonylamino group.
  • examples thereof include an azolyl group such as a group or an imidazole-1-yl group or a pyrazole-1-yl group.
  • Step 4-1 The diphenylmethaneimine derivative (XV) can be obtained by a coupling reaction between the 6-haloquinoline derivative (IX-a) and diphenylmethaneimine in the presence of a metal catalyst and a base.
  • the selection conditions for the reagent, catalyst, hydrogen pressure, reaction solvent, and reaction temperature in this step are the same as in Step 2-1.
  • the 6-haloquinoline derivative (IX-a) used in the coupling reaction can be purchased, or can be produced by the method described in Steps 1-1 to 1-3, a known method, or a method similar thereto. Can be done.
  • Step 4-2 The aminoquinoline derivative (XVI) can be obtained by the deprotection reaction of the diphenylmethaneimine derivative (XV).
  • Examples of the acid used for the deprotection reaction include hydrochloric acid, 10 wt% hydrogen chloride / methanol solution, 4 mol / L hydrogen chloride / ethyl acetate solution, trifluoroacetic acid, and hydrofluoric acid, but hydrochloric acid is preferable.
  • the amount of acid used in the deprotection reaction is preferably 0.5 to 100 equivalents with respect to the diphenylmethaneimine derivative (XV), and more preferably 1 to 10 equivalents.
  • the reaction solvent for the deprotection reaction is appropriately selected depending on the type of reagent used and the like, but is not particularly limited as long as it does not inhibit the reaction, and is not particularly limited, for example, diethyl ether, THF, DME or 1,4-dioxane and the like.
  • examples thereof include an ether solvent, an ester solvent such as ethyl acetate or propyl acetate, a chlorine solvent such as dichloromethane, chloroform or 1,2-dichloroethane, an alcohol solvent such as methanol or ethanol, or a mixed solvent thereof.
  • Ester solvents such as ethyl or propyl acetate or chlorine solvents such as dichloromethane, chloroform or 1,2-dichloroethane are preferred.
  • the reaction temperature of the deprotection reaction is preferably 0 to 200 ° C, more preferably 0 to 100 ° C.
  • the reaction time of the deprotection reaction varies depending on the reaction conditions, but is preferably 1 to 48 hours.
  • the amide quinoline derivative (XVIII) can be obtained by an acylation reaction between the aminoquinoline derivative (XVI) and the acylating agent (XVII).
  • the amount of the acylating agent (XVII) used in the acylation reaction is preferably 0.5 to 10 equivalents, more preferably 1 to 3 equivalents, relative to the aminoquinoline derivative (XVI).
  • the acylation reaction may use a base if desired.
  • the base used include organic bases such as triethylamine, N, N-diisopropylethylamine or pyridine, hydroxides of alkali metals such as sodium hydroxide, potassium hydroxide or lithium hydroxide, sodium hydrogencarbonate or potassium hydrogencarbonate and the like.
  • Alkali metal hydrogen carbonates, alkali metal carbonates such as sodium carbonate and potassium carbonate, or mixtures thereof may be mentioned, but alkali metal hydroxides such as sodium hydroxide, potassium hydroxide or lithium hydroxide are preferable.
  • the reaction solvent used for the acylation reaction is appropriately selected depending on the type of the reagent used, but is not particularly limited as long as it does not inhibit the reaction.
  • a nitrile solvent such as acetonitrile or propionitrile, DMF.
  • DMA or DMSO or other aprotonic polar solvent diethyl ether, THF, DME or 1,4-dioxane or other ether solvent, ethyl acetate or propyl acetate or other ester solvent, acetone or methyl ethyl ketone or other ketone solvent, Examples thereof include water or a mixed solvent thereof, and a mixed solvent of water and an ether solvent such as diethyl ether, THF, DME or 1,4-dioxane is preferable.
  • the reaction temperature of the acylation reaction is preferably ⁇ 78 ° C. to 100 ° C., more preferably ⁇ 20 ° C. to 50 ° C.
  • the reaction time of the acylation reaction varies depending on the reaction conditions, but is preferably 1 to 30 hours.
  • the acylating agent (XVII) used in the acylation reaction can be purchased, or can be produced by a known method or a method similar thereto.
  • Step 4-4 The tetrahydroquinoline derivative (Id) can be obtained by a hydrogenation reaction or a hydrogen transfer reduction reaction of the amide quinoline derivative (XVIII).
  • the selection conditions for the reagent, catalyst, hydrogen pressure, reaction solvent, and reaction temperature in this step are the same as in steps 1-4.
  • the urea quinoline derivative (XX) can be obtained by a urea conversion reaction between the aminoquinoline derivative (XVI) and the urea agent (XIX).
  • the amount of the urea agent (XIX) used in the urea conversion reaction is preferably 0.5 to 10 equivalents, more preferably 1 to 3 equivalents, relative to the aminoquinoline derivative (XVI).
  • a base may be used for the urea conversion reaction if desired.
  • the base used include organic bases such as triethylamine, N, N-diisopropylethylamine or pyridine, hydroxides of alkali metals such as sodium hydroxide, potassium hydroxide or lithium hydroxide, sodium hydrogencarbonate or potassium hydrogencarbonate and the like.
  • Alkali metal carbonates such as hydrogen carbonate, sodium carbonate, potassium carbonate and the like, or mixtures thereof can be mentioned, but organic bases such as triethylamine, N, N-diisopropylethylamine or pyridine are preferable.
  • the reaction solvent used for the urea conversion reaction is appropriately selected depending on the type of the reagent used, but is not particularly limited as long as it does not inhibit the reaction.
  • a nitrile solvent such as acetonitrile or propionitrile, DMF.
  • DMA or DMSO and other aprotonic polar solvents diethyl ether, THF, DME or 1,4-dioxane and other ether solvents, ethyl acetate or propyl acetate and other ester solvents, acetone or methyl ethyl ketone and other ketone solvents, Examples thereof include water or a mixed solvent thereof, but an ether solvent such as diethyl ether, THF, DME or 1,4-dioxane is preferable.
  • the reaction temperature of the urea conversion reaction is preferably ⁇ 78 ° C. to 100 ° C., more preferably ⁇ 20 ° C. to 50 ° C.
  • the reaction time of the urea conversion reaction varies depending on the reaction conditions, but is preferably 1 to 30 hours.
  • the urea agent (XIX) used for the urea conversion reaction can be purchased, or can be produced by a known method or a method similar thereto.
  • Step 4-6 The tetrahydroquinoline derivative (Ie) can be obtained by a hydrogenation reaction or a hydrogen transfer reduction reaction of the urea quinoline derivative (XX).
  • the selection conditions for the reagent, catalyst, hydrogen pressure, reaction solvent, and reaction temperature in this step are the same as in steps 1-4.
  • the sulfonylamide quinoline derivative (XXII) can be obtained by a sulfonylation reaction between the aminoquinoline derivative (XVI) and the sulfonylating agent (XXI).
  • the amount of the sulfonylating agent (XXI) used in the sulfonylation reaction is preferably 0.5 to 10 equivalents with respect to the aminoquinoline derivative (XVI), more preferably 1 to 3 equivalents.
  • the sulfonylation reaction may use a base if desired.
  • the base used include organic bases such as triethylamine, N, N-diisopropylethylamine or pyridine, hydroxides of alkali metals such as sodium hydroxide, potassium hydroxide or lithium hydroxide, sodium hydrogencarbonate or potassium hydrogencarbonate and the like.
  • Alkali metal carbonates such as hydrogen carbonate, sodium carbonate, potassium carbonate and the like, or mixtures thereof can be mentioned, but organic bases such as triethylamine, N, N-diisopropylethylamine or pyridine are preferable.
  • the reaction solvent used for the sulfonylation reaction is appropriately selected depending on the type of the reagent used, but is not particularly limited as long as it does not inhibit the reaction.
  • a nitrile solvent such as acetonitrile or propionitrile, DMF.
  • DMA or DMSO and other aprotonic polar solvents diethyl ether, THF, DME or 1,4-dioxane and other ether solvents, ethyl acetate or propyl acetate and other ester solvents, acetone or methyl ethyl ketone and other ketone solvents, Examples thereof include water or a mixed solvent thereof, but an ether solvent such as diethyl ether, THF, DME or 1,4-dioxane is preferable.
  • the reaction temperature of the sulfonylation reaction is preferably ⁇ 78 ° C. to 100 ° C., more preferably ⁇ 20 ° C. to 50 ° C.
  • the reaction time of the sulfonylation reaction varies depending on the reaction conditions, but is preferably 1 to 30 hours.
  • the sulfonylating agent (XXI) used in the sulfonylation reaction can be purchased, or can be produced by a known method or a method similar thereto.
  • Step 4-8 The tetrahydroquinoline derivative (If) can be obtained by a hydrogenation reaction or a hydrogen transfer reduction reaction of the sulfonylamide quinoline derivative (XXII).
  • the selection conditions for the reagent, catalyst, hydrogen pressure, reaction solvent, and reaction temperature in this step are the same as in steps 1-4.
  • Step 5-1 The methoxycarbonyltetrahydroquinoline derivative (XXIII) can be obtained by hydrogenation reaction or hydrogen transfer reduction reaction of the quinoline-6-carboxylic acid ester derivative (IX-b).
  • the selection conditions for the reagent, catalyst, hydrogen pressure, reaction solvent, and reaction temperature in this step are the same as in steps 1-4.
  • the quinoline-6-carboxylic acid ester derivative (IX-b) used for the hydrogenation reaction or the hydrogen transfer reduction reaction can be purchased, or the method according to Steps 1-1 to 1-3, a known method. Alternatively, it can be manufactured by a method similar thereto.
  • Step 5-2 The hydroxymethyltetrahydroquinoline derivative (XXIV) can be obtained by a reduction reaction of the methoxycarbonyltetrahydroquinoline derivative (XXIII).
  • Examples of the reducing agent used in the reduction reaction include an aluminum-based reducing agent such as lithium aluminum hydride or diisobutyl aluminum hydride, and a boron-based reducing agent such as sodium borohydride or lithium borohydride.
  • Aluminum-based reducing agents such as aluminum or diisobutylaluminum hydride are preferred.
  • the amount of the reducing agent used in the reduction reaction is preferably 0.3 to 100 equivalents, more preferably 0.5 to 20 equivalents, relative to the methoxycarbonyltetrahydroquinoline derivative (XXIII).
  • the reaction solvent used for the reduction reaction is appropriately selected depending on the type of the reagent used, but is not particularly limited as long as it does not inhibit the reaction, and is, for example, methanol, ethanol, isopropyl alcohol, tert-butyl alcohol and the like.
  • Alcohol-based solvent aprotonic polar solvent such as DMF, DMA or DMSO, ether-based solvent such as diethyl ether, THF, DME or 1,4-dioxane, chlorine-based solvent such as dichloromethane, chloroform or 1,2-dichloroethane, Examples thereof include aromatic hydrocarbon solvents such as toluene or xylene or mixed solvents thereof, and ether solvents such as diethyl ether, THF, DME or 1,4-dioxane, or aromatic hydrocarbon solvents such as toluene or xylene. Solvents are preferred.
  • the reaction temperature of the reduction reaction is preferably ⁇ 100 ° C. to 200 ° C., more preferably ⁇ 50 ° C. to 50 ° C.
  • the reaction time of the reduction reaction varies depending on the reaction conditions, but is preferably 1 to 30 hours.
  • the tetrahydroquinoline derivative (Ig) can be obtained by a substitution reaction between the hydroxymethyltetrahydroquinoline derivative (XXIV) and the secondary amine derivative (XXV) in the presence of the phosphine derivative and iodine.
  • the amount of the secondary amine derivative (XXV) used in the substitution reaction is preferably 0.5 to 100 equivalents, more preferably 1 to 20 equivalents, relative to the hydroxymethyltetrahydroquinoline derivative (XXIV).
  • Examples of the phosphine derivative used in the substitution reaction include triphenylphosphine, trimethylphosphine and tri-n-butylphosphine, with triphenylphosphine being preferred.
  • the amount of the phosphine derivative used in the substitution reaction is preferably 0.5 to 20 equivalents, more preferably 1 to 5 equivalents, relative to the hydroxymethyltetrahydroquinoline derivative (XXIV).
  • the amount of iodine used in the substitution reaction is preferably 0.5 to 20 equivalents, more preferably 1 to 5 equivalents, relative to the hydroxymethyltetrahydroquinoline derivative (XXIV).
  • the reaction solvent used for the substitution reaction is not particularly limited as long as it does not inhibit the reaction, and is, for example, an aprotonic polar solvent such as DMF, DMA or DMSO, a ketone solvent such as acetone or methyl ethyl ketone, ethyl acetate or acetic acid.
  • an aprotonic polar solvent such as DMF, DMA or DMSO
  • a ketone solvent such as acetone or methyl ethyl ketone, ethyl acetate or acetic acid.
  • Ester solvent such as propyl, ether solvent such as diethyl ether, THF, DME or 1,4-dioxane, chlorine solvent such as dichloromethane, chloroform or 1,2-dichloroethane, aromatic hydrocarbon solvent such as toluene or xylene Examples thereof include a solvent or a mixed solvent thereof, and a chlorine-based solvent such as dichloromethane, chloroform or 1,2-dichloroethane is preferable.
  • the reaction temperature of the substitution reaction is preferably 0 to 150 ° C, more preferably 10 to 70 ° C.
  • the reaction time of the substitution reaction varies depending on the reaction conditions, but is preferably 1 to 24 hours.
  • the nitrile derivative (XXVI) can be obtained by a Mitsunobu reaction between a hydroxymethyltetrahydroquinoline derivative (XXIV) and acetone cyanohydrin using an azodicarboxylic acid ester derivative in the presence of a phosphine derivative.
  • Examples of the azodicarboxylate derivative used in the Mitsunobu reaction include diethyl azodicarboxylate, diisopropyl azodicarboxylate, and 1,1'-(azodicarbonyl) dipiperidin, but 1,1'-(azodicarbonyl). Dipiperidin is preferred.
  • the amount of the azodicarboxylic acid ester derivative used in the Mitsunobu reaction is preferably 0.5 to 30 equivalents, more preferably 1 to 10 equivalents, relative to the hydroxymethyltetrahydroquinoline derivative (XXIV).
  • Examples of the phosphine derivative used in the Mitsunobu reaction include triphenylphosphine, trimethylphosphine and tri-n-butylphosphine, with tri-n-butylphosphine being preferred.
  • the amount of the phosphine derivative used in the Mitsunobu reaction is preferably 0.5 to 30 equivalents, more preferably 1 to 10 equivalents, relative to the hydroxymethyltetrahydroquinoline derivative (XXIV).
  • the amount of acetone cyanohydrin used in the Mitsunobu reaction is preferably 0.5 to 50 equivalents, more preferably 1 to 20 equivalents, relative to the hydroxymethyltetrahydroquinoline derivative (XXIV).
  • the reaction solvent used for the Mitsunobu reaction is not particularly limited as long as it does not inhibit the reaction, and is, for example, an aprotonic polar solvent such as DMF, DMA or DMSO, a ketone solvent such as acetone or methyl ethyl ketone, ethyl acetate or acetic acid.
  • an aprotonic polar solvent such as DMF, DMA or DMSO
  • a ketone solvent such as acetone or methyl ethyl ketone, ethyl acetate or acetic acid.
  • Ester solvent such as propyl, ether solvent such as diethyl ether, THF, DME or 1,4-dioxane, chlorine solvent such as dichloromethane, chloroform or 1,2-dichloroethane, aromatic hydrocarbon solvent such as toluene or xylene
  • ether solvent such as diethyl ether, THF, DME or 1,4-dioxane
  • chlorine solvent such as dichloromethane, chloroform or 1,2-dichloroethane
  • aromatic hydrocarbon solvent such as toluene or xylene
  • an ether solvent such as diethyl ether, THF, DME or 1,4-dioxane is preferable.
  • the reaction temperature of the Mitsunobu reaction is preferably ⁇ 20 ° C. to 200 ° C., more preferably ⁇ 10 ° C. to 100 ° C.
  • the reaction time of the Mitsunobu reaction varies depending on the reaction conditions, but is preferably 1 to 12 hours.
  • Step 6-2 The tetrahydroquinoline derivative (Ih) can be obtained by a hydrolysis reaction with a nitrile derivative (XXVI) in the presence of a hydrogen peroxide solution and a base.
  • the amount of hydrogen peroxide solution used in the hydrolysis reaction is preferably 0.5 to 100 equivalents with respect to the nitrile derivative (XXVI), and more preferably 1 to 30 equivalents.
  • Examples of the base used for the hydrolysis reaction include lithium hydroxide, potassium hydroxide, sodium hydroxide or sodium tert-butoxide, with potassium hydroxide or sodium hydroxide being preferred.
  • the amount of the base used in the hydrolysis reaction is preferably 0.5 to 100 equivalents, more preferably 0.8 to 20 equivalents, relative to the nitrile derivative (XXVI).
  • the reaction solvent used for the hydrolysis reaction is appropriately selected depending on the type of the reagent used, but is not particularly limited as long as it does not inhibit the reaction, and is, for example, an ether solvent such as THF, 1,4-dioxane or DME. Solvents, chlorine-based solvents such as dichloromethane, chloroform or 1,2-dichloroethane, aromatic hydrocarbon-based solvents such as benzene or toluene, aprotonic polar solvents such as DMF, DMA or DMSO, and ketone solvents such as acetone or methyl ethyl ketone.
  • an ether solvent such as THF, 1,4-dioxane or DME.
  • Solvents chlorine-based solvents such as dichloromethane, chloroform or 1,2-dichloroethane
  • aromatic hydrocarbon-based solvents such as benzene or toluene
  • aprotonic polar solvents such as DMF, D
  • An alcohol solvent such as methanol, ethanol or 2-propanol or a mixed solvent thereof, and an aprotonic polar solvent such as DMF, DMA or DMSO and an ether solvent such as THF, 1,4-dioxane or DME.
  • a mixed solvent with is preferable.
  • the reaction temperature of the hydrolysis reaction is preferably ⁇ 50 ° C. to 150 ° C., more preferably ⁇ 20 ° C. to 100 ° C.
  • the reaction time of the hydrolysis reaction is appropriately selected according to conditions such as the reaction temperature, but is preferably 1 to 30 hours.
  • the carboxylic acid derivative (XXVII) can be obtained by the hydrolysis reaction of the tetrahydroquinoline derivative (Ih) in the presence of a base.
  • Examples of the base used for the hydrolysis reaction include lithium hydroxide, potassium hydroxide, sodium hydroxide or sodium tert-butoxide, with potassium hydroxide or sodium hydroxide being preferred.
  • the amount of the base used in the hydrolysis reaction is preferably 0.5 to 100 equivalents, more preferably 0.8 to 30 equivalents, relative to the tetrahydroquinoline derivative (Ih).
  • the reaction solvent used for the hydrolysis reaction is appropriately selected depending on the type of the reagent used, but is not particularly limited as long as it does not inhibit the reaction, and is, for example, an ether solvent such as THF, 1,4-dioxane or DME. Solvents, chlorine-based solvents such as dichloromethane, chloroform or 1,2-dichloroethane, aromatic hydrocarbon-based solvents such as benzene or toluene, aprotonic polar solvents such as DMF, DMA or DMSO, and ketone solvents such as acetone or methyl ethyl ketone. , An alcohol solvent such as methanol, ethanol or 2-propanol, water or a mixed solvent thereof, and a mixed solvent of an alcohol solvent such as methanol, ethanol or 2-propanol and water is preferable.
  • an ether solvent such as THF, 1,4-dioxane or DME.
  • Solvents chlorine-based solvents such as
  • the reaction temperature of the hydrolysis reaction is preferably 0 to 200 ° C, more preferably 20 ° C to 100 ° C.
  • the reaction time of the hydrolysis reaction is appropriately selected according to conditions such as the reaction temperature, but is preferably 1 to 30 hours.
  • the tetrahydroquinoline derivative (Ii) can be obtained by a condensation reaction between a carboxylic acid derivative (XXVII) and an amine derivative (XXVIII) in the presence of a condensing agent.
  • the amount of the amine derivative (XXVIII) used in the condensation reaction is preferably 0.1 to 10 equivalents, more preferably 0.5 to 5 equivalents, relative to the carboxylic acid derivative (XXVII).
  • Examples of the condensing agent used in the condensation reaction include N, N'-dicyclohexylcarbodiimide, N-ethyl-N'-3-dimethylaminopropylcarbodiimide hydrochloride, N, N'-carbodiimidazole, ⁇ [(1-(1- Cyano-2-ethoxy-2-oxoethylidene) amino] oxy ⁇ -4-morpholinomethylene ⁇ dimethylammonium hexafluorophosphate, O- (7-azabenzotriazole-1-yl) -1,1,3,3 -Tetramethyluronium hexafluorophosphate or O- (benzotriazole-1-yl) -N, N, N', N'-tetramethyluronium hexafluorophosphate can be mentioned, but O- (7-aza). Benzotriazole-1-yl) -1,1,3,3-tetramethyluronium hexaflu
  • the amount of the condensing agent used in the condensation reaction is preferably 0.5 to 10 equivalents with respect to the carboxylic acid derivative (XXVII), more preferably 1 to 3 equivalents.
  • Examples of the base used in the condensation reaction include organic bases such as triethylamine or diisopropylethylamine, inorganic bases such as sodium hydrogencarbonate or potassium carbonate, metal hydride compounds such as sodium hydride, potassium hydride or calcium hydride, and methyllithium.
  • organic bases such as triethylamine or diisopropylethylamine
  • inorganic bases such as sodium hydrogencarbonate or potassium carbonate
  • metal hydride compounds such as sodium hydride, potassium hydride or calcium hydride
  • methyllithium Alternatively, alkyl lithium such as butyl lithium, lithium amide such as lithium hexamethyldisilazide or lithium diisopropylamide or a mixture thereof can be mentioned, but an organic base such as triethylamine or diisopropylethylamine is preferable.
  • the amount of the base used in the condensation reaction is preferably 0.5 to 10 equivalents with respect to the carboxylic acid derivative (XXVII), more preferably 1 to 5 equivalents.
  • the amine derivative (XXVIII) may be used as the base used in the condensation reaction, and when the amine derivative (XXVIII) is used as the base used in the condensation reaction, the amount of the amine derivative (XXVIII) is the carboxylic acid derivative (XXVII). On the other hand, 0.6 to 20 equivalents are preferable, and 1 to 10 equivalents are more preferable.
  • the reaction solvent used for the condensation reaction is appropriately selected depending on the type of the reagent used and the like, but is not particularly limited as long as it does not inhibit the reaction.
  • an ether solvent such as THF, 1,4-dioxane or DME is used.
  • examples thereof include a solvent, a chlorine-based solvent such as dichloromethane, chloroform or 1,2-dichloroethane, an aprotonic polar solvent such as DMF or DMSO, or a nitrile-based solvent such as acetonitrile or propionitrile, and examples thereof include dichloromethane, chloroform or 1,2.
  • -A chlorine-based solvent such as dichloroethane or an aprotonic polar solvent such as DMF or DMSO is preferable.
  • the reaction temperature of the condensation reaction is preferably 0 to 200 ° C, more preferably 20 to 100 ° C.
  • the reaction time of the condensation reaction is appropriately selected according to conditions such as the reaction temperature, but is preferably 1 to 30 hours.
  • the amine derivative (XXVIII) used in the condensation reaction may be a free form or a salt such as hydrochloride.
  • the amine derivative (XXVIII) used in the condensation reaction can be purchased, or can be produced by a known method or a method similar thereto.
  • the optically active substances (I-j') and (I-j'') of the tetrahydroquinoline derivative (I) are 1,4-dihydro-2,6-dimethyl-3,5-in the presence of an asymmetric phosphate catalyst. It can be obtained by an asymmetric hydrogen transfer reduction reaction between a pyridine dicarboxylic acid ester derivative and a quinoline derivative (XXIX). For example, it can be carried out according to the method described in (Tetrahedron: Asymmetry, 2015, pp. 1174-1179), or a method similar thereto.
  • the quinoline derivative (XXIX) used for the asymmetric hydrogen transfer reduction reaction can be purchased, or Step 1-1 to Step 1-3, Step 2-1 and Step 3-1 and Step 3-2. It can be produced by the method described in 4-1 to Step 4-3, Step 4-5 and Step 4-7, a known method or a method thereof.
  • Examples of the asymmetric phosphoric acid catalyst used for the asymmetric hydrogen transfer reduction reaction include hydrogen phosphate (S) -1,1'-binaphthalene-2,2'-diyl and hydrogen phosphate (R) -1,1'. -Vinaphthalene-2,2'-diyl, hydrogen phosphate (S) -3,3'-bis (3,5-bis (trifluoromethyl) phenyl) -1,1'-binaphthyl-2,2'-diyl , Hydrogen (R) -3,3'-bis (3,5-bis (trifluoromethyl) phenyl) -1,1'-binaphthyl-2,2'-diyl, hydrogen phosphate (S) -3 , 3'-bis (triphenylsilyl) -1,1'-binaphthyl-2,2'-diyl, hydrogen phosphate (R) -3,3'-bis (triphenyl
  • Step 8-1 The quinoline derivative (XXXII) can be obtained by a coupling reaction between the 3-haloquinoline derivative (XXX) and the boronic acid derivative (XXXI) in the presence of a metal catalyst and a base.
  • the selection conditions for the reagent, catalyst, hydrogen pressure, reaction solvent, and reaction temperature in this step are the same as in Step 1-1.
  • the 3-haloquinoline derivative (XXX) and the boronic acid derivative (XXXI) used in the coupling reaction can be purchased or can be produced by a known method or a method similar thereto.
  • Step 8-2 The tetrahydroquinoline derivative (Ik) can be obtained by a hydrogenation reaction or a hydrogen transfer reduction reaction of the quinoline derivative (XXXII).
  • the selection conditions for the reagent, catalyst, hydrogen pressure, reaction solvent, and reaction temperature in this step are the same as in steps 1-4.
  • optically active substances (Ik') and (Ik'') of the tetrahydroquinoline derivative (Ik) can be obtained by HPLC fractionation using a chiral column.
  • the medicine of the present invention can be used as a medicine for treating or preventing a disease, disorder or syndrome related to ferrotosis inhibition.
  • “Inhibition of ferroptosis” means to inhibit ferroptosis (cell death controlled in a divalent iron-dependent manner).
  • the ferrotosis inhibitor of the present invention can be used for a disease, disorder or syndrome in which improvement of pathological condition or remission of symptoms can be expected by inhibiting ferrotosis.
  • Disease, disorder or syndrome related to ferroptosis inhibition means a disease, disorder or syndrome in which improvement of pathological condition or symptom remission can be expected by the above-mentioned ferroptosis inhibition.
  • Diseases, disorders or syndromes associated with the above ferrotosis inhibition include, for example, renal disease, Parkinson's disease, Alzheimer's disease, Huntington's disease, non-alcoholic fatty hepatitis, chronic obstructive pulmonary disease, Friedreich's ataxia or multiple sclerosis. Sexual sclerosis is mentioned, and multiple sclerosis is preferable.
  • Multiple sclerosis is characterized by demyelination in which the myelin sheath that covers nerve fibers such as the brain, spinal cord, and optic nerve is destroyed, and the disorder progresses while repeating recurrence and remission.
  • the symptom varies depending on the lesion site and shows various neurological symptoms such as visual impairment, paralysis of limbs, sensory impairment and gait disturbance. Examples of multiple sclerosis include relapsing-remitting multiple sclerosis, primary advanced multiple sclerosis, and secondary advanced multiple sclerosis.
  • the tetrahydroquinoline derivative (I) of the present invention or a pharmacologically acceptable salt thereof or a pharmaceutical product contains a tetrahydroquinoline derivative (I) or a pharmacologically acceptable salt thereof as an active ingredient for ferrotosis inhibition. It can also be used as an agent.
  • the ferrotosis inhibitor is a tetrahydroquinoline derivative (I) or a pharmacologically acceptable salt thereof, or 2-phenyl-1,2,3,4-tetrahydroquinoline or a pharmacologically acceptable salt thereof. Salt can be used.
  • the "ferroptosis inhibitor” means a compound having an action of improving cell viability and improving and maintaining cell function by inhibiting ferroptosis, or a composition containing the compound as an active ingredient.
  • Patent Document 1 and Non-Patent Document 11 disclose that a tetrahydroquinoxaline derivative has a strong radical scavenging action.
  • Non-Patent Document 11 reports that the tetrahydroquinoline derivative has an extremely weak radical scavenging action.
  • the tetrahydroquinoline derivative (I) of the present invention or a pharmacologically acceptable salt thereof exhibits a ferrotosis inhibitory effect, and thus treats or prevents diseases, disorders or syndromes related to ferrotosis inhibition. It can be used as a new medicine to do so.
  • the ferrotosis-inhibiting effect of the tetrahydroquinoline derivative (I) or its pharmacologically acceptable salt can be evaluated using an in vitro test. For example, by treating established cells such as human fibrosarcoma cells (HT-1080 cells), primary cultured cells, iPS cells and the like with ferrotosis inducers such as Erastin, RSL3, FIN56 or butionin sulfoximin. The inhibitory effect on cell death that occurs can be evaluated as an index.
  • the radical scavenging effect of the test compound can be evaluated using an in vitro test. For example, it can be evaluated by a method using the stable radical 1,1-Diphenyl-2-picrylydrazyl (DPPH) (Antioxidants, 2019, Vol. 258).
  • DPPH stable radical 1,1-Diphenyl-2-picrylydrazyl
  • tetrahydroquinoline derivative (I) or a pharmacologically acceptable salt thereof is effective in treating or preventing a disease, disorder or syndrome associated with ferrotosis inhibition.
  • the pathological model include an experimental autoimmune encephalomyelitis model (Journal of Neuroscience Research, 2006, Vol. 84, p.1225-1234, International Immunology, 1997, Vol. 9, p.1243-1251. ).
  • MOG myelin oligodendrocyte glycoprotein
  • proteolipid protein or their partial peptides to control hindlimb paralysis due to demyelination of the central nervous system. It is an animal model that induces neuropathy.
  • the above pathological model is widely used for examining the efficacy of therapeutic agents or preventive agents for multiple sclerosis because of its symptoms and pathological findings similar to those of humans. Efficacy for the treatment or prevention of multiple sclerosis is evaluated using, for example, a decrease in the neurological symptom score, which is a characteristic index of multiple sclerosis, using the above experimental autoimmune encephalomyelitis model. be able to.
  • tetrahydroquinoline derivative (I) or a pharmacologically acceptable salt thereof has a ferrotosis inhibitory effect
  • mammals eg, mice, rats, hamsters, rabbits, cats, dogs, cows, sheep, monkeys or humans
  • Can be used as a useful drug particularly, therapeutic or preventive use for diseases, disorders or syndromes related to inhibition of ferrotosis such as multiple sclerosis).
  • the tetrahydroquinoline derivative (I) or its pharmacologically acceptable salt is used clinically as a pharmaceutical product
  • the tetrahydroquinoline derivative (I) or its pharmacologically acceptable salt is used as it is or pharmacologically.
  • the above-mentioned medicines include excipients, binders, lubricants, disintegrants, sweeteners, stabilizers, flavoring agents, fragrances, coloring agents, fluidizing agents, preservatives, buffers, and solubilizing agents, as required.
  • Additives such as agents, emulsifiers, surfactants, suspending agents, diluents or tonicity agents may be appropriately mixed.
  • Pharmacologically acceptable carriers include these additives.
  • the above-mentioned pharmaceutical products can be produced by a conventional method by appropriately using these pharmacologically acceptable carriers.
  • the administration form of the above-mentioned pharmaceuticals includes, for example, oral preparations such as tablets, pills, capsules, granules, powders, syrups, emulsions or suspensions, inhalants, injections, suppositories or liquids. Examples include oral preparations, or ointments, creams or patches for topical administration.
  • a suitable base eg, fatty acid polymer, glycolic acid polymer, buty acid-glycolic acid copolymer, fatty acid polymer and glycolic acid polymer mixture or polyglycerol fatty acid ester. Therefore, it is also effective to use a sustained-release preparation.
  • the preparation of the above-mentioned preparation containing the above-mentioned tetrahydroquinoline derivative (I) or a pharmacologically acceptable salt thereof can be carried out according to a known production method generally used in the field of preparation.
  • the preparation of tablets can be carried out by containing, for example, an excipient, a binder, a disintegrant, a lubricant, etc.
  • the preparation of pills and granules can be carried out, for example, by containing an excipient, a binder, a disintegrant.
  • the capsule and the powder can be prepared by containing, for example, an excipient, and the syrup can be prepared by containing, for example, a sweetener.
  • the emulsion and the suspending agent can be prepared by containing, for example, a surfactant, a suspending agent, an emulsifier and the like.
  • excipient examples include lactose, glucose, starch, sucrose, microcrystalline cellulose, citrus powder, mannitol, sodium hydrogencarbonate, calcium phosphate or calcium sulfate.
  • binder examples include starch paste solution, Arabic rubber solution, gelatin solution, tragant solution, carboxymethyl cellulose solution, sodium alginate solution and glycerin.
  • disintegrant examples include starch or calcium carbonate.
  • lubricant examples include magnesium stearate, calcium stearate, polyethylene glycol, purified talc or silica.
  • sweetener examples include glucose, fructose, invert sugar, sorbitol, xylitol, glycerin or simple syrup.
  • surfactant examples include sodium lauryl sulfate, polysorbate 80, sorbitan monofatty acid ester, and polyoxyl 40 stearate.
  • suspending agent examples include gum arabic, sodium alginate, sodium carboxymethyl cellulose, methyl cellulose or bentonite.
  • Examples of the above emulsifier include gum arabic, tragant, gelatin or polysorbate 80.
  • a pharmaceutical product containing a tetrahydroquinoline derivative (I) or a pharmacologically acceptable salt thereof is prepared in the above dosage form, a colorant, a preservative, or a fragrance commonly used in the pharmaceutical field is used.
  • a flavoring agent, a stabilizer, a thickening agent and the like can be appropriately added.
  • the above-mentioned pharmaceutical product preferably contains the tetrahydroquinoline derivative (I) or a pharmacologically acceptable salt thereof in an amount of 0.00001 to 90% by weight, more preferably 0.01 to 70% by weight.
  • the daily dose of the above-mentioned drug is appropriately selected depending on the patient's condition, body weight, age, administration route, etc.
  • the amount of the active ingredient for an adult is 1 mg in the case of an oral preparation. It is preferable to administer up to 1000 mg, and if it is an injection, 0.01 to 100 mg, and each can be administered once or in several divided doses.
  • the above-mentioned drugs may be used in combination or in combination with other drugs in order to supplement or enhance the therapeutic or preventive effect or reduce the dose.
  • the above-mentioned medicines may be administered at the same time as other drugs, or may be continuously administered in any order.
  • Other drugs may be used in combination with, for example, the following drugs for treating multiple sclerosis and drugs for treating symptoms such as convulsions and spasticity in patients with multiple sclerosis, but are limited thereto. Not done.
  • drugs for treating other multiple sclerosis include corticosteroids (prednisolone, methylprednisolone, etc.) and interferon preparations (interferon ⁇ , interferon ⁇ -1b, interferon ⁇ -1a, PEG-interferon ⁇ -1a, etc.).
  • corticosteroids prednisolone, methylprednisolone, etc.
  • interferon preparations interferon ⁇ , interferon ⁇ -1b, interferon ⁇ -1a, PEG-interferon ⁇ -1a, etc.
  • Gratiramer acetate fumaric acid compound (dimethyl fumarate, diloxymethyl fumarate, monomethyl fumarate), teriflunomide, S1P receptor agonists (fingolimod, siponimodo, ozanimod, ponesimod), anti- ⁇ 4 integulin antibody (natarizumab), anti-CD20 antibody (Oclerizumab, Ofatumumab), anti-CD52 antibody (Alemtumab), cladribine, mitoxanthrone, Breton-type tyrosine kinase inhibitor, immunomodulators (methotrexate, azathiopurine, cyclophosphamide, cyclosporin A, tachlorimus, misolibin, leflunomide, etc.), Copolymer I, immunoglobulins, T cell receptor vaccines, adhesion molecule inhibitors, painkillers (indomethacin, diclofenac, etc.
  • agents for treating symptoms such as convulsions and convulsions in patients with multiple sclerosis include anticonvulsants (carbamazepine, phenytoin, clonazepam, amitryptin, etc.).
  • Root temperature in the following examples and reference examples usually indicates about 10 to about 35 ° C.
  • the solvent name shown in the NMR data indicates the solvent used for the measurement.
  • the 400 MHz NMR spectrum was measured using a JNM-ECS400 type nuclear magnetic resonance apparatus or a JNM-ECZ400S type nuclear magnetic resonance apparatus (JEOL Ltd.). The chemical shift is expressed in ⁇ (unit: ppm) with reference to tetramethylsilane, and the signals are s (single line), d (double line), t (triple line), q (quadruple line), and quint, respectively.
  • Silica gel 60 (Merck & Co., Ltd.) was used as silica gel, (Fuji Silysia Chemical Ltd.) was used as amino silica gel, and YFLCW-prep2XY (Yamazen) was used for flash chromatography. Silica gel 60 (Merck & Co., Inc.) was used for preparative thin layer chromatography (hereinafter, preparative TLC).
  • the obtained crude product was purified by column chromatography (silica gel, hexane / ethyl acetate), and the title compound (hereinafter referred to as the compound of Example 2) (95.0 mg, 0.457 mmol, yield 95%, enantiomeric excess) was purified. 98.5% ee) was obtained as a colorless transparent oil.
  • Example 8 7-methoxy-2- (4-methoxyphenyl) quinoline (62.0 mg, 0.234 mmol) synthesized in Reference Example 4, the title compound (hereinafter referred to as Example 8) was used in the same manner as in Example 4. Compound) (62.3 mg, 0.234 mmol, 99% yield) was obtained as a white solid.
  • Example 10 2- (2- (trifluoromethyl) phenyl) quinoline (62.0 mg, 0.227 mmol) synthesized in Reference Example 6, the title compound (hereinafter referred to as Example 10) was used in the same manner as in Example 4.
  • Compound) (52.2 mg, 0.188 mmol, yield 83%) was obtained as a colorless transparent oil.
  • the obtained crude product was purified by column chromatography (silica gel, chloroform / methanol) and column chromatography (amino silica gel, hexane / ethyl acetate) to give the title compound in the upper row (hereinafter referred to as the compound of Example 14) (4). .1 mg, 0.019 mmol, yield 15%) was obtained as a colorless transparent oil.
  • Example 15 2- (6-methoxypyridin-3-yl) quinoline (50.0 mg, 0.212 mmol) synthesized in Reference Example 8, the title compound (hereinafter referred to as Example 15) was used in the same manner as in Example 4. Compound) (11.0 mg, 0.0458 mmol, yield 22%) was obtained as a colorless transparent oil.
  • Methyl 4- (1,2,3,4-tetrahydroquinoline-2-yl) benzoate (50.0 mg, 0.187 mmol) synthesized in Example 17 was dissolved in THF (1.9 mL) and then ice. Under cooling, a methyllithium THF solution (0.56 mL, 0.65 mmol) was added dropwise, and the mixture was stirred under ice-cooling for 2 hours. After completion of the reaction, water was added to the reaction mixture, and the reaction mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure.
  • the obtained crude product was purified by column chromatography (silica gel, hexane / ethyl acetate) to make the title compound (hereinafter, the compound of Example 18) (13.1 mg, 0.0490 mmol, yield 26%) colorless. Obtained as a clear oil.
  • Example 19 the title compound (hereinafter referred to as the compound of Example 19) (hereinafter, the compound of Example 19) was used in the same manner as in Example 4. 118 mg, 0.409 mmol, 89% yield) was obtained as a colorless transparent oil.
  • Example 13 N- (4- (quinoline-2-yl) phenyl) acetamide (40.0 mg, 0.152 mmol) synthesized in Reference Example 13, the title compound (hereinafter referred to as Example) was used in the same manner as in Example 4. 21 compounds) (6.60 mg, 24.8 ⁇ mol, yield 16%) were obtained as white amorphous.
  • Example 23 Using 3', 4'-dihydro- [2,6'-biquinolin] -2'(1'H) -one (118 mg, 0.431 mmol) synthesized in Reference Example 15, the same method as in Example 4 was used.
  • the title compound (hereinafter referred to as the compound of Example 23) (80.6 mg, 0.290 mmol, yield 67%) was obtained as a white solid.
  • Example 4 using 1'-methyl-3', 4'-dihydro- [2,6'-biquinolin] -2'(1'H) -one (171 mg, 0.593 mmol) synthesized in Reference Example 16.
  • the title compound (hereinafter, the compound of Example 24) (54.3 mg, 0.186 mmol, yield 31%) was obtained as a white solid by the same method as in the above.
  • Example 17 Using 5- (quinoline-2-yl) isoindoline-1-one (61.6 mg, 0.237 mmol) synthesized in Reference Example 17, the title compound (hereinafter referred to as Example) was used in the same manner as in Example 4. 25 compounds) (35.7 mg, 0.135 mmol, 57% yield) were obtained as a white solid.
  • Example 29 2- (4- (trifluoromethyl) phenyl) quinoline (80.0 mg, 0.293 mmol) synthesized in Reference Example 21, the title compound (hereinafter referred to as Example 29) was used in the same manner as in Example 26.
  • Compound) (77.0 mg, 0.278 mmol, yield 95%) was obtained as a colorless transparent oil.
  • Example 30 2- (3- (trifluoromethyl) phenyl) quinoline (40.0 mg, 0.146 mmol) synthesized in Reference Example 22, the title compound (hereinafter referred to as Example 30) was used in the same manner as in Example 26. Compound) (39.1 mg, 0.141 mmol, yield 96%) was obtained as a colorless transparent oil.
  • DMSO / THF (1/4, v / v, 1.37 mmol) of 4- (1,2,3,4-tetrahydroquinoline-2-yl) benzonitrile synthesized in Example 35 was added. After dissolving in 4 mL), a 1 mol / L aqueous sodium hydroxide solution (300 ⁇ L, 0.300 mmol) and a 30% aqueous hydrogen peroxide solution (23 ⁇ L, 0.300 mmol) were added, and the mixture was stirred at room temperature for 2 hours. A 10% aqueous sodium thiosulfate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate.
  • Methyl 4- (1,2,3,4-tetrahydroquinoline-2-yl) benzoate synthesized in Example 17 (545 mg, 2.04 mmol) was dissolved in THF / methanol (5.0 mL / 5.0 mL). , 8 mol / L aqueous sodium hydroxide solution (0.764 mL, 6.11 mmol) was added, and the mixture was stirred at room temperature for 20 hours under an argon atmosphere. After completion of the reaction, saturated aqueous ammonium chloride solution was added to the reaction mixture, the mixture was concentrated under reduced pressure, and the mixture was extracted with ethyl acetate.
  • Example 49 Using (4- (quinoline-2-yl) phenyl) methanol (136 mg, 0.576 mmol) synthesized in Reference Example 32, the title compound (hereinafter, the compound of Example 49) was used in the same manner as in Example 26. (77.3 mg, 0.323 mmol, 56% yield) was obtained as a pale yellow oil.
  • Methyl 2-phenylquinoline-5-carboxylate (60.0 mg, 0.228 mmol) was dissolved in toluene (1 mL) under an argon atmosphere, and a 1.0 mol / L diisobutylaluminum / hexane solution (0. (912 mL, 0.912 mmol) was added, and the mixture was stirred at ⁇ 78 ° C. for 1.5 hours. After completion of the reaction, the temperature of the reaction mixture was raised to 0 ° C., a saturated aqueous solution of potassium sodium tartrate was added to the reaction mixture, the mixture was stirred at room temperature for 16 hours, and the aqueous layer was extracted with ethyl acetate.
  • Example 51 Using the (2-phenylquinoline-5-yl) methanol (51.7 mg, 0.220 mmol) synthesized in Reference Example 34, the title compound (hereinafter referred to as the compound of Example 51) was used in the same manner as in Example 26. (47.2 mg, 0.197 mmol, 90% yield) was obtained as a pale yellow solid.
  • Methyl 2-chloroquinoline-6-carboxylate (100 mg, 0.451 mmol) is dissolved in THF (2 mL) and a 1 mol / L methylmagnesium bromide / THF solution (1.35 mL, 1.35 mmol) is added under an argon atmosphere -78. The mixture was added at ° C. and stirred at room temperature for 3 hours. After completion of the reaction, saturated aqueous ammonium chloride solution was added to the reaction mixture until the pH reached 6-7, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure.
  • Methyl 2-phenyl-1,2,3,4-tetrahydroquinoline-6-carboxylate (25.0 mg, 93.5 ⁇ mol) synthesized in Example 56 was dissolved in THF (1 mL) and 1 mol / L methylmagnesium bromide. / THF solution (0.374 mL, 0.374 mmol) was added at 0 ° C. under an argon atmosphere and stirred at room temperature for 16 hours. After completion of the reaction, water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure.
  • the obtained crude product is purified by thin layer preparative chromatography (hexane / ethyl acetate), and the title compound (hereinafter referred to as the compound of Example 57) (3.70 mg, 13.8 ⁇ mol, yield 15%) is diluted. Obtained as a yellow amorphous.
  • Methyl 2-phenyl-1,2,3,4-tetrahydroquinoline-6-carboxylate (38.0 mg, 0.142 mmol) synthesized in Example 56 was dissolved in toluene (2.0 mL) and then -78.
  • a 1.01 mol / L hydrided diisobutylaluminum / toluene solution (0.426 mL, 0.426 mmol) was slowly added dropwise at ° C. under an argon atmosphere. The reaction mixture was then slowly warmed to room temperature and stirred for 6 hours. After completion of the reaction, an aqueous sodium potassium tartrate solution (8 mL) was added, and the mixture was stirred overnight at room temperature.
  • Acetone cyanohydrin (2-phenyl-1,2,3,4-tetrahydroquinoline-6-yl) methanol (100 mg, 0.418 mmol) synthesized in Example 58 was dissolved in THF (4.2 mL). 114 ⁇ L, 1.25 mmol) and tri-n-butylphosphine (207 ⁇ L, 0.836 mmol) were added. Under ice-cooling, 1,1'-(azodicarbonyl) dipiperidine (211 mg, 0.836 mmol) was added, and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate.
  • Methyl 2-phenylquinoline-6-carboxylate (0.279 g, 1.06 mmol) synthesized in Reference Example 38 was dissolved in a THF / methanol solution (10 mL), and a 1 mol / L sodium hydroxide aqueous solution (2.12 mL, 2) was dissolved. .12 mmol) was added, and the mixture was stirred at room temperature for 17 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. 1 mol / L hydrochloric acid (4 mL) was added to the obtained crude product, and the precipitated solid was collected by filtration.
  • Example 4 Using tert-butyl carbamic acid (72.0 mg, 0.225 mmol) synthesized in Reference Example 42, the title compound (hereinafter referred to as Example) was used in the same manner as in Example 4. 63 compounds) (29.0 mg, 0.0895 mmol, yield 40%) were obtained as a white solid.
  • the obtained crude product was purified by column chromatography (silica gel, hexane / ethyl acetate) to make the title compound (hereinafter, the compound of Example 71) (49.2 mg, 0.174 mmol, yield 69%) colorless. Obtained as a clear oil.
  • 6-bromo-2-phenylquinoline (60.0 mg, 0.211 mmol) synthesized in Reference Example 49, cesium carbonate (241 mg, 0.739 mmol), palladium (II) acetate (4.74 mg, 21.1 ⁇ mol), 2 , 2'-Bis (diphenylphosphino) -1,1'-binaphthyl (26.3 mg, 42.2 ⁇ mol) was suspended in 1,4-dioxane (2.10 mL) and piperidine (69.7 ⁇ L, 0. 633 mmol) was added, and the mixture was stirred at 100 ° C. for 15 hours under an argon atmosphere. After completion of the reaction, water was added to the reaction mixture and the mixture was extracted with chloroform.
  • the obtained crude product was purified by column chromatography (silica gel, hexane / ethyl acetate), and the title compound (hereinafter referred to as the compound of Example 72) (6.00 mg, 20.5 ⁇ mol, yield 22%) was used as a brown solid. Obtained as.
  • 1,1-Diphenyl-N- (2-phenylquinoline-6-yl) methaneimine (108 mg, 0.280 mmol) synthesized in Reference Example 52 was dissolved in THF (1.0 mL) and 2 mol / L hydrochloric acid (0. 420 mL, 0.840 mmol) was added, and the mixture was stirred at room temperature for 1 hour. After completion of the reaction, a saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layers were combined, dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure.

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WO2023249105A1 (ja) * 2022-06-24 2023-12-28 東レ株式会社 薬剤性心筋障害の治療剤又は予防剤
WO2023249106A1 (ja) * 2022-06-24 2023-12-28 東レ株式会社 筋萎縮性側索硬化症の治療剤又は予防剤
WO2023249107A1 (ja) * 2022-06-24 2023-12-28 東レ株式会社 末梢神経障害の治療剤又は予防剤

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WO2023249105A1 (ja) * 2022-06-24 2023-12-28 東レ株式会社 薬剤性心筋障害の治療剤又は予防剤
WO2023249106A1 (ja) * 2022-06-24 2023-12-28 東レ株式会社 筋萎縮性側索硬化症の治療剤又は予防剤
WO2023249107A1 (ja) * 2022-06-24 2023-12-28 東レ株式会社 末梢神経障害の治療剤又は予防剤

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